Abstract:
The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit of U.S. Provisional Application Ser. No. 62/297,495, filed 19 Feb. 2016, and Great Britain Application No. 1602918.3, filed 19 Feb. 2016, the content of each of these applications is herein incorporated by reference in their entirety. 
         [0002]    This application also is related to PCT/EP2017/053704 filed 17 Feb. 2017, the content of which is incorporated herein by reference in its entirety. 
     
    
     REFERENCE TO SEQUENCE LISTING SUBMITTED AS A COMPLIANT ASCII TEXT FILE (.TXT) 
       [0003]    Pursuant to the EFS-Web legal framework and 37 CFR §§1.821-825 (see MPEP §2442.03(a)), a Sequence Listing in the form of an ASCII-compliant text file (entitled “Sequence_Listing_2912919-062001_ST25.txt” created on 16 Feb. 2017, and 51,091 bytes in size) is submitted concurrently with the instant application, and the entire contents of the Sequence Listing are incorporated herein by reference. 
       FIELD 
       [0004]    The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 
         [0005]    The present invention relates to several novel peptide sequences and their variants derived from HLA class I molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses, or as targets for the development of pharmaceutically/immunologically active compounds and cells. 
       BACKGROUND OF THE INVENTION 
       [0006]    Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoproliferative diseases. NHL usually originates in lymphoid tissues and can spread to other organs (National Cancer Institute, 2015). 
         [0007]    NHL is the seventh most common type of cancer and represents 4.3% of all new cancer cases in the U.S. (SEER Stat facts, 2014). It is the most common hematological malignancy both in Europe and the U.S. (Inoges et al., 2014). 
         [0008]    The probability to develop NHL increases with age: The median age at the time point of diagnosis is 66 years. NHL is more common in people of Caucasian descent (21 cases per 100,000 persons), followed by Africans (15 cases per 100,000 persons) and Asians (14 cases per 100,000 persons). Men have a higher risk to develop NHL than women (23.9 cases per 100,000 males vs. 16.3 cases per 100,000 females) (SEER Stat facts, 2014). 
         [0009]    The 5-year relative survival of NHL patients is 70% and varies with the cancer stage at the time point of diagnosis. For localized disease, the 5-year relative survival is 82%. If NHL has spread to different parts of the body, the 5-year relative survival decreases to 73.8% for regional and 62.4% for distant stage disease (SEER Stat facts, 2014). Risk factors include (high) age, male gender, ethnicity (Caucasian), exposure to benzene or radiation, HIV, autoimmune diseases, infections with HTLV-1, EBV or HHV8, infections with  Helicobacter pylori, Chlamydophila psittaci, Campylobacter jejuni  or HCV, (high) body weight and breast implants (American Cancer Society, 2015). 
         [0010]    NHL has over 60 subtypes. The three most common subtypes are diffuse large B-cell lymphoma (DLBCL, the most common subtype), follicular lymphoma (FL, the second most common subtype) and small lymphocytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL, the third most common subtype). DLBCL, FL and SLL/CLL account for about 85% of NHL (Li et al., 2015). 
         [0011]    Diffuse large B-cell lymphoma (DLBCL) is the most common NHL type and comprises 30% of all NHLs. DLBCL belongs to the aggressive NHL subtypes and most patients show a quickly progressing disease. The International Prognostic Index (IPI) for aggressive NHL uses five significant risk factors prognostic for overall survival: 
         [0000]    1. Age (≦60 years vs.&gt;60 years)
 
2. Serum lactate dehydrogenase (LDH) (normal vs. elevated)
 
3. Performance status (0 or 1 vs. 2-4)
 
4. Stage (stage I or II vs. stage III or IV)
 
5. Extranodal site involvement (0 or 1 vs. 2-4).
 
         [0012]    Patients with two or more risk factors have a less than 50% chance of relapse-free survival and overall survival at 5 years. Patients with rearrangements of the bcl-2 and myc gene and/or overexpression of myc have a particularly poor prognosis. DLBCL patients co-expressing CD20 and CD30 have a more favorable prognosis and are predestined for an anti-CD30-specific therapy (National Cancer Institute, 2015). 
         [0013]    Follicular lymphoma (FL) is the second most common NHL type and comprises 20% of all NHLs and 70% of all indolent lymphomas. More than 90% of the patients exhibit rearrangement of the bcl-2 gene. Most patients are 50 years or older at the time point of diagnosis and have advanced stage disease. The Follicular Lymphoma International Prognostic Index (FLIPI) uses five significant risk factors prognostic for overall survival: 
         [0000]    1. Age (≦60 years vs.&gt;60 years)
 
2. Serum lactate dehydrogenase (LDH) (normal vs. elevated)
 
3. Stage (stage I or II vs. stage III or IV)
 
4. Hemoglobin level (≧120 g/L vs.&lt;120 g/L)
 
5. Number of nodal areas (≦vs.&gt;4).
 
         [0014]    Patients with none or one risk factor have an 85% 10-year survival rate. Patients with three or more risk factors have a 40% 10-year survival rate (National Cancer Institute, 2015). 
         [0015]    Diagnosis of NHL is done on an excisional biopsy of an abnormal lymph node or an incisional biopsy of an involved organ. Besides immunohistochemistry, cytogenetics, molecular genetics and fluorescent in situ hybridization (FISH) are used to clarify the diagnosis (Armitage, 2007). 
         [0016]    Staging is done after the evaluation of the patients&#39; history, physical examination and laboratory studies including hematologic parameters, screening chemistry studies and especially a test for serum lactate dehydrogenase (LDH) level. Imaging studies include computed tomograms of the chest, abdomen and pelvis and a PET scan (Armitage, 2007). 
         [0017]    Determining for prognosis and treatment decision is the differentiation between indolent NHL types and aggressive NHLs. Indolent NHLs progress slowly, have a good prognosis and respond in early stages to radiation therapy, chemotherapy and immunotherapy, but are not curable in advanced stages. Aggressive NHLs progress quickly, but are responsive to intensive combination chemotherapy (National Cancer Institute, 2015). 
         [0018]    Depending on the disease stage at the time point of diagnosis patients are classified into prognostic groups (National Cancer Institute, 2015) as follows: 
         [0000]    
       
         
               
               
             
           
               
                   
               
               
                 Stage 
                 Prognostic groups 
               
               
                   
               
             
             
               
                 I 
                 Involvement of a single lymphatic site (nodal region, Waldeyer 
               
               
                   
                 ring, thymus or spleen (I). 
               
               
                   
                 Localized involvement of a single extra-lymphatic organ or site 
               
               
                   
                 in the absence of any lymph node involvement (IE). 
               
               
                 II 
                 Involvement of two or more lymph node regions on the same side 
               
               
                   
                 of the diaphragm (II). 
               
               
                   
                 Localized involvement of a single extra-lymphatic organ or site in 
               
               
                   
                 association with regional lymph node involvement with or without 
               
               
                   
                 involvement of other lymph node regions on the same side of the 
               
               
                   
                 diaphragm (IIE). The number of regions involved may be indicated 
               
               
                   
                 by a subscript Arabic numeral (for example II3). 
               
               
                 III 
                 Involvement of lymph node regions on both sides of the diaphragm 
               
               
                   
                 (III), which also may be accompanied by extra-lymphatic extension 
               
               
                   
                 in association with adjacent lymph node involvement (IIIE) or by 
               
               
                   
                 involvement of the spleen (IIIS) or both (IIIE, IIIS). 
               
               
                 IV 
                 Diffuse or disseminated involvement of one or more extra- 
               
               
                   
                 lymphatic organs, with or without associated lymph node 
               
               
                   
                 involvement. 
               
               
                   
                 Isolated extra-lymphatic organ involvement in the absence of 
               
               
                   
                 adjacent regional lymph node involvement, but in conjunction with 
               
               
                   
                 disease in distant site(s). Stage IV includes any involvement of the 
               
               
                   
                 liver or bone marrow, lungs (other than by direct extension from 
               
               
                   
                 another site), or cerebrospinal fluid. 
               
               
                   
               
             
          
         
       
     
         [0019]    The Ann Arbor staging system is usually used for patients with NHL. In this system, stage I, stage II, stage III and stage IV are sub-classified in to the categories A and B. Patients with well-defined generalized symptoms receive the designation B, while patients without these symptoms belong to category A. Category B symptoms include unexplained loss of more than 10% of body weight in the six months before diagnosis, unexplained fever with temperatures above 38° C. and drenching night sweats. Specialized designations are used depending on the involvement of specific organs/sites (National Cancer Institute, 2015) as follows: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Designation 
                 Specific sites 
               
               
                   
                   
               
             
             
               
                   
                 E 
                 Extranodal lymphoid malignancies near 
               
               
                   
                   
                 major lymphatic aggregates 
               
               
                   
                 N 
                 Nodes 
               
               
                   
                 H 
                 Liver 
               
               
                   
                 L 
                 Lung 
               
               
                   
                 M 
                 Bone marrow 
               
               
                   
                 S 
                 Spleen 
               
               
                   
                 P 
                 Pleura 
               
               
                   
                 O 
                 Bone 
               
               
                   
                 D 
                 Skin 
               
               
                   
                   
               
             
          
         
       
     
         [0020]    To assign a precise stage, patients receive a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings of invasive procedures beyond the initial biopsy (National Cancer Institute, 2015). 
         [0021]    Treatment of NHL depends on the histologic type and stage. Standard treatment options include (National Cancer Institute, 2015): 
         [0000]    
       
         
               
               
             
           
               
                   
               
               
                 Stage 
                 Standard treatment option 
               
               
                   
               
             
             
               
                 Indolent, 
                 Radiation therapy 
               
               
                 stage I and contiguous 
                 Rituximab ± chemotherapy 
               
               
                 stage II NHL 
                 Watchful waiting 
               
               
                   
                 Other therapies as designated for 
               
               
                   
                 patients with advanced-stage disease 
               
               
                 Indolent, 
                 Watchful waiting for asymptomatic 
               
               
                 non-contiguous stage 
                 patients 
               
               
                 II/III/IV NHL 
                 Rituximab 
               
               
                   
                 Purine nucleoside analogs 
               
               
                   
                 Alkylating agents ± steroids 
               
               
                   
                 Combination chemotherapy 
               
               
                   
                 Yttrium-90-labeled ibritumomab tiuxetan 
               
               
                   
                 Maintenance rituximab 
               
               
                 Indolent, 
                 Chemotherapy (single agent or 
               
               
                 Recurrent NHL 
                 combination) 
               
               
                   
                 Rituximab 
               
               
                   
                 Lenalidomide 
               
               
                   
                 Radiolabeled anti-CD20 monoclonal 
               
               
                   
                 antibodies 
               
               
                   
                 Palliative radiation therapy 
               
               
                 Aggressive, 
                 R-CHOP ± (involved-field radiation 
               
               
                 stage I and contiguous 
                 therapy) IF-XRT 
               
               
                 stage II NHL 
               
               
                 Aggressive, 
                 R-CHOP 
               
               
                 non-contiguous stage 
                 Other combination chemotherapy 
               
               
                 II/III/IV NHL 
               
               
                 Lymphoblastic lymphoma 
                 Intensive therapy 
               
               
                   
                 Radiation therapy 
               
               
                 Diffuse, small, noncleaved- 
                 Aggressive multi-drug regimens 
               
               
                 cell/Burkitt lymphoma 
                 Central nervous system (CNS) prophylaxis 
               
               
                 Aggressive, 
                 Bone marrow or stem cell transplantation 
               
               
                 recurrent NHL 
                 Re-treatment with standard agents 
               
               
                   
                 Palliative radiation therapy 
               
               
                   
               
             
          
         
       
     
         [0022]    Indolent, stage I and contiguous stage II NHL: Standard treatment options include radiation therapy, rituximab (anti-CD20 monoclonal antibody)±chemotherapy, watchful waiting and other therapies as designated for patients with advanced-stage disease. 
         [0023]    Indolent, non-contiguous stage II/III/IV NHL: Standard treatment options include watchful waiting for asymptomatic patients, rituximab, obinutuzumab (anti-CD20 monoclonal antibody), purine nucleoside analogs (fludarabine, 2-chlorodeoxyadenosine), alkylating agents (cyclophosphamide, chlorambucil)±steroids, bendamustine, combination chemotherapy (CVP, C-MOPP (cyclophosphamide, vincristine, procarbazine, and prednisone), CHOP, FND (fludarabine, mitoxantrone±dexamethasone)), yttrium-labeled ibritumomab tiuxetan and maintenance rituximab. Rituximab (R) is considered first-line therapy, either alone or in combination with other agents (R-Bendamustine, R-F (fludarabine), R-CVP (cyclophosphamide, vincristine, and prednisone), R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FM (fludarabine, mitoxantrone), R-FCM (fludarabine, cyclophosphamide, and mitoxantrone)). Under clinical evaluation are bone marrow transplantation (BMT) or peripheral stem cell transplantation (PSCT), idiotype vaccines and radiolabeled monoclonal antibodies (ofatumumab: anti-CD20 monoclonal antibody). 
         [0024]    Indolent, recurrent NHL: Standard treatment options include chemotherapy (single agent or combination), rituximab, lenalidomide, radiolabeled anti-CD20 monoclonal antibodies (yttrium-90 ibritumomab) and palliative radiation therapy. Treatment options under clinical evaluation include SCTs. 
         [0025]    Aggressive, stage I and contiguous stage II NHL: Standard treatment options include R-CHOP±IF-XRT. Treatment options under clinical evaluation include R-ACVBP (rituximab+doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone). 
         [0026]    Aggressive, non-contiguous stage II/III/1V NHL: Standard treatment options include combination chemotherapy±local-field radiation therapy. Drug combinations include ACVBP, CHOP, CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisone), m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, leucovorin), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone fixed dose, bleomycin, leucovorin), ProMACE CytaBOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin), R-CHOP. Under clinical evaluation are BMT and SCT. 
         [0027]    Lymphoblastic lymphoma: Standard treatment options include intensive therapy and radiation therapy. 
         [0028]    Diffuse, small noncleaved-cell/Burkitt lymphoma: Standard treatment options include aggressive multidrug regimens and CNS prophylaxis. 
         [0029]    Aggressive, recurrent NHL: Standard treatment options include BMT or SCT, re-treatment with standard agents (rituximab, radiolabeled anti-CD20 monoclonal antibodies, denileukin diftitox (a fusion protein combining diphtheria toxin and interleukin-2)) and palliative radiation therapy. Treatment options under clinical evaluation include SCT (National Cancer Institute, 2015). 
         [0030]    Spontaneous tumor regression can be observed in lymphoma patients. Therefore, active immunotherapy is a therapy option (Palomba, 2012). An important vaccination option includes Id vaccines. B lymphocytes express surface immunoglobulins with a specific amino acid sequence in the variable regions of their heavy and light chains, unique to each cell clone (=idiotype, Id). The idiotype functions as a tumor associated antigen. 
         [0031]    Passive immunization includes the injection of recombinant murine anti-Id monoclonal antibodies alone or in combination with IFN alpha, IL2 or chlorambucil. 
         [0032]    Active immunization includes the injection of recombinant protein (Id) conjugated to an adjuvant (KLH), given together with GM-CSF as an immune adjuvant. Tumor-specific Id is produced by hybridoma cultures or using recombinant DNA technology (plasmids) by bacterial, insect or mammalian cell culture. 
         [0033]    Three phase III clinical trials have been conducted (Biovest, Genitope, Favrille). In two trials patients had received rituximab. GM-CSF was administered in all three trials. Biovest used hybridoma-produced protein, Genitope and Favrille used recombinant protein. In all three trials Id was conjugated to KLH. Only Biovest had a significant result. 
         [0034]    Vaccines other than Id include the cancer-testis antigens MAGE, NY-ESO1 and PASD-1, the B-cell antigen CD20 or cellular vaccines. The vaccines consist of DCs pulsed with apoptotic tumor cells, tumor cell lysate, DC-tumor cell fusion or DCs pulsed with tumor-derived RNA. In situ vaccination involves the vaccination with intra-tumoral CpG in combination with chemotherapy or irradiated tumor cells grown in the presence of GM-CSF and collection/expansion/re-infusion of T cells. 
         [0035]    Vaccinations with antibodies that alter immunologic checkpoints are comprised of anti-CD40, anti-OX40, anti-41BB, anti-CD27, anti-GITR (agonist antibodies that directly enhance anti-tumor response) or anti-PD1, anti-CTLA-4 (blocking antibodies that inhibit the checkpoint that would hinder the immune response). Examples are ipilimumab (anti-CTLA-4) and CT-011 (anti-PD1) (Palomba, 2012). 
         [0036]    Considering the severe side-effects and expense associated with treating cancer, there is a need to identify factors that can be used in the treatment of cancer in general and NHL in particular. There is also a need to identify factors representing biomarkers for cancer in general and NHL in particular, leading to better diagnosis of cancer, assessment of prognosis, and prediction of treatment success. 
         [0037]    Immunotherapy of cancer represents an option of specific targeting of cancer cells while minimizing side effects. Cancer immunotherapy makes use of the existence of tumor associated antigens. 
         [0038]    The current classification of tumor associated antigens (TAAs) comprises the following major groups: 
         [0000]    a) Cancer-testis antigens: The first TAAs ever identified that can be recognized by T cells belong to this class, which was originally called cancer-testis (CT) antigens because of the expression of its members in histologically different human tumors and, among normal tissues, only in spermatocytes/spermatogonia of testis and, occasionally, in placenta. Since the cells of testis do not express class I and II HLA molecules, these antigens cannot be recognized by T cells in normal tissues and can therefore be considered as immunologically tumor-specific. Well-known examples for CT antigens are the MAGE family members and NY-ESO-1.
 
b) Differentiation antigens: These TAAs are shared between tumors and the normal tissue from which the tumor arose. Most of the known differentiation antigens are found in melanomas and normal melanocytes. Many of these melanocyte lineage-related proteins are involved in biosynthesis of melanin and are therefore not tumor specific but nevertheless are widely used for cancer immunotherapy. Examples include, but are not limited to, tyrosinase and Melan-A/MART-1 for melanoma or PSA for prostate cancer.
 
c) Over-expressed TAAs: Genes encoding widely expressed TAAs have been detected in histologically different types of tumors as well as in many normal tissues, generally with lower expression levels. It is possible that many of the epitopes processed and potentially presented by normal tissues are below the threshold level for T-cell recognition, while their over-expression in tumor cells can trigger an anticancer response by breaking previously established tolerance. Prominent examples for this class of TAAs are Her-2/neu, survivin, telomerase, or WT1.
 
d) Tumor-specific antigens: These unique TAAs arise from mutations of normal genes (such as β-catenin, CDK4, etc.). Some of these molecular changes are associated with neoplastic transformation and/or progression. Tumor-specific antigens are generally able to induce strong immune responses without bearing the risk for autoimmune reactions against normal tissues. On the other hand, these TAAs are in most cases only relevant to the exact tumor on which they were identified and are usually not shared between many individual tumors. Tumor-specificity (or -association) of a peptide may also arise if the peptide originates from a tumor- (-associated) exon in case of proteins with tumor-specific (-associated) isoforms.
 
e) TAAs arising from abnormal post-translational modifications: Such TAAs may arise from proteins which are neither specific nor overexpressed in tumors but nevertheless become tumor associated by posttranslational processes primarily active in tumors. Examples for this class arise from altered glycosylation patterns leading to novel epitopes in tumors as for MUC1 or events like protein splicing during degradation which may or may not be tumor specific.
 
f) Oncoviral proteins: These TAAs are viral proteins that may play a critical role in the oncogenic process and, because they are foreign (not of human origin), they can evoke a T-cell response. Examples of such proteins are the human papilloma type 16 virus proteins, E6 and E7, which are expressed in cervical carcinoma.
 
         [0039]    T-cell based immunotherapy targets peptide epitopes derived from tumor-associated or tumor-specific proteins, which are presented by molecules of the major histocompatibility complex (MHC). The antigens that are recognized by the tumor specific T lymphocytes, that is, the epitopes thereof, can be molecules derived from all protein classes, such as enzymes, receptors, transcription factors, etc. which are expressed and, as compared to unaltered cells of the same origin, usually up-regulated in cells of the respective tumor. 
         [0040]    There are two classes of MHC-molecules, MHC class I and MHC class II. MHC class I molecules are composed of an alpha heavy chain and beta-2-microglobulin, MHC class II molecules of an alpha and a beta chain. Their three-dimensional conformation results in a binding groove, which is used for non-covalent interaction with peptides. 
         [0041]    MHC class I molecules can be found on most nucleated cells. They present peptides that result from proteolytic cleavage of predominantly endogenous proteins, defective ribosomal products (DRIPs) and larger peptides. However, peptides derived from endosomal compartments or exogenous sources are also frequently found on MHC class I molecules. This non-classical way of class I presentation is referred to as cross-presentation in the literature (Brossart and Bevan, 1997; Rock et al., 1990). MHC class II molecules can be found predominantly on professional antigen presenting cells (APCs), and primarily present peptides of exogenous or transmembrane proteins that are taken up by APCs e.g. during endocytosis, and are subsequently processed. Complexes of peptide and MHC class I are recognized by CD8-positive T cells bearing the appropriate T-cell receptor (TCR), whereas complexes of peptide and MHC class II molecules are recognized by CD4-positive-helper-T cells bearing the appropriate TCR. It is well known that the TCR, the peptide and the MHC are thereby present in a stoichiometric amount of 1:1:1. 
         [0042]    CD4-positive helper T cells play an important role in inducing and sustaining effective responses by CD8-positive cytotoxic T cells. The identification of CD4-positive T-cell epitopes derived from tumor associated antigens (TAA) is of great importance for the development of pharmaceutical products for triggering anti-tumor immune responses (Gnjatic et al., 2003). At the tumor site, T helper cells, support a cytotoxic T cell- (CTL-) friendly cytokine milieu (Mortara et al., 2006) and attract effector cells, e.g. CTLs, natural killer (NK) cells, macrophages, and granulocytes (Hwang et al., 2007). 
         [0043]    In the absence of inflammation, expression of MHC class II molecules is mainly restricted to cells of the immune system, especially professional antigen-presenting cells (APC), e.g., monocytes, monocyte-derived cells, macrophages, dendritic cells. In cancer patients, cells of the tumor have been found to express MHC class II molecules (Dengjel et al., 2006). 
         [0044]    Elongated (longer) peptides of the invention can act as MHC class II active epitopes. T-helper cells, activated by MHC class II epitopes, play an important role in orchestrating the effector function of CTLs in anti-tumor immunity. T-helper cell epitopes that trigger a T-helper cell response of the TH1 type support effector functions of CD8-positive killer T cells, which include cytotoxic functions directed against tumor cells displaying tumor-associated peptide/MHC complexes on their cell surfaces. In this way tumor-associated T-helper cell peptide epitopes, alone or in combination with other tumor-associated peptides, can serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. 
         [0045]    It was shown in mammalian animal models, e.g., mice, that even in the absence of CD8-positive T lymphocytes, CD4-positive T cells are sufficient for inhibiting manifestation of tumors via inhibition of angiogenesis by secretion of interferon-gamma (IFNγ) (Beatty and Paterson, 2001; Mumberg et al., 1999). There is evidence for CD4 T cells as direct anti-tumor effectors (Braumuller et al., 2013; Tran et al., 2014). 
         [0046]    Since the constitutive expression of HLA class II molecules is usually limited to immune cells, the possibility of isolating class II peptides directly from primary tumors was previously not considered possible. However, Dengjel et al. were successful in identifying a number of MHC Class II epitopes directly from tumors (WO 2007/028574, EP 1 760 088 B1). 
         [0047]    Since both types of response, CD8 and CD4 dependent, contribute jointly and synergistically to the anti-tumor effect, the identification and characterization of tumor-associated antigens recognized by either CD8+ T cells (ligand: MHC class I molecule+peptide epitope) or by CD4-positive T-helper cells (ligand: MHC class II molecule+peptide epitope) is important in the development of tumor vaccines. 
         [0048]    For an MHC class I peptide to trigger (elicit) a cellular immune response, it also must bind to an MHC-molecule. This process is dependent on the allele of the MHC-molecule and specific polymorphisms of the amino acid sequence of the peptide. MHC-class-1-binding peptides are usually 8-12 amino acid residues in length and usually contain two conserved residues (“anchors”) in their sequence that interact with the corresponding binding groove of the MHC-molecule. In this way, each MHC allele has a “binding motif” determining which peptides can bind specifically to the binding groove. 
         [0049]    In the MHC class I dependent immune reaction, peptides not only have to be able to bind to certain MHC class I molecules expressed by tumor cells, they subsequently also have to be recognized by T cells bearing specific T cell receptors (TCR). 
         [0050]    For proteins to be recognized by T-lymphocytes as tumor-specific or -associated antigens, and to be used in a therapy, particular prerequisites must be fulfilled. The antigen should be expressed mainly by tumor cells and not, or in comparably small amounts, by normal healthy tissues. In a preferred embodiment, the peptide should be over-presented by tumor cells as compared to normal healthy tissues. It is furthermore desirable that the respective antigen is not only present in a type of tumor, but also in high concentrations (i.e. copy numbers of the respective peptide per cell). Tumor-specific and tumor-associated antigens are often derived from proteins directly involved in transformation of a normal cell to a tumor cell due to their function, e.g. in cell cycle control or suppression of apoptosis. Additionally, downstream targets of the proteins directly causative for a transformation may be up-regulated and thus may be indirectly tumor-associated. Such indirect tumor-associated antigens may also be targets of a vaccination approach (Singh-Jasuja et al., 2004). It is essential that epitopes are present in the amino acid sequence of the antigen, in order to ensure that such a peptide (“immunogenic peptide”), being derived from a tumor associated antigen, leads to an in vitro or in vivo T-cell-response. 
         [0051]    Basically, any peptide able to bind an MHC molecule may function as a T-cell epitope. A prerequisite for the induction of an in vitro or in vivo T-cell-response is the presence of a T cell having a corresponding TCR and the absence of immunological tolerance for this particular epitope. 
         [0052]    Therefore, TAAs are a starting point for the development of a T cell based therapy including but not limited to tumor vaccines. The methods for identifying and characterizing the TAAs are usually based on the use of T-cells that can be isolated from patients or healthy subjects, or they are based on the generation of differential transcription profiles or differential peptide expression patterns between tumors and normal tissues. However, the identification of genes over-expressed in tumor tissues or human tumor cell lines, or selectively expressed in such tissues or cell lines, does not provide precise information as to the use of the antigens being transcribed from these genes in an immune therapy. This is because only an individual subpopulation of epitopes of these antigens are suitable for such an application, since a T cell with a corresponding TCR has to be present and the immunological tolerance for this particular epitope needs to be absent or minimal. In a very preferred embodiment of the invention it is therefore important to select only those over- or selectively presented peptides against which a functional and/or a proliferating T cell can be found. Such a functional T cell is defined as a T cell, which upon stimulation with a specific antigen can be clonally expanded and is able to execute effector functions (“effector T cell”). 
         [0053]    In case of targeting peptide-MHC by specific TCRs (e.g. soluble TCRs) and antibodies or other binding molecules (scaffolds) according to the invention, the immunogenicity of the underlying peptides is secondary. In these cases, the presentation is the determining factor. 
       BRIEF SUMMARY OF THE INVENTION 
       [0054]    In a first aspect of the present invention, the present invention relates to a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 311 or a variant sequence thereof which is at least 77%, preferably at least 88%, homologous (preferably at least 77% or at least 88% identical) to SEQ ID NO: 1 to SEQ ID NO: 311, wherein said variant binds to MHC and/or induces T cells cross-reacting with said peptide, or a pharmaceutical acceptable salt thereof, wherein said peptide is not the underlying full-length polypeptide. 
         [0055]    The present invention further relates to a peptide of the present invention comprising a sequence that is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 311 or a variant thereof, which is at least 77%, preferably at least 88%, homologous (preferably at least 77% or at least 88% identical) to SEQ ID NO: 1 to SEQ ID NO: 311, wherein said peptide or variant thereof has an overall length of between 8 and 100, preferably between 8 and 30, and most preferred of between 8 and 14 amino acids. 
         [0056]    The following tables show the peptides according to the present invention, their respective SEQ ID NOs, and the prospective source (underlying) genes for these peptides. All peptides in Table 1 and Table 2 bind to HLA-A*02. The peptides in Table 2 have been disclosed before in large listings as results of high-throughput screenings with high error rates or calculated using algorithms, but have not been associated with cancer at all before. The peptides in Table 3 are additional peptides that may be useful in combination with the other peptides of the invention. The peptides in Tables 4A and B are furthermore useful in the diagnosis and/or treatment of various other malignancies that involve an over-expression or over-presentation of the respective underlying polypeptide. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Peptides according to the present invention. 
               
               
                 SEQ ID 
               
             
          
           
               
                 No. 
                 Sequence 
                 GeneID(s) 
                 Official Gene Symbol(s) 
               
               
                   
               
             
          
           
               
                 1 
                 LLSGQLPTI 
                 84969 
                 TOX2 
               
               
                   
               
               
                 2 
                 LLSEETPSA 
                 10765 
                 KDM5B 
               
               
                   
               
               
                 3 
                 LTIDTQYYL 
                 5422 
                 POLA1 
               
               
                   
               
               
                 4 
                 TLLGFFLAKV 
                 5422 
                 POLA1 
               
               
                   
               
               
                 5 
                 VLQGLTFTL 
                 6890 
                 TAP1 
               
               
                   
               
               
                 6 
                 TLITLPLLFL 
                 6890 
                 TAP1 
               
               
                   
               
               
                 7 
                 NLLGMIFSM 
                 51398 
                 WDR83OS 
               
               
                   
               
               
                 8 
                 ALYAVIEKA 
                 5293 
                 PIK3CD 
               
               
                   
               
               
                 9 
                 FLLDLDPLL 
                 7915 
                 ALDH5A1 
               
               
                   
               
               
                 10 
                 FLLVGTQIDL 
                 643751, 998 
                 CDC42P6, CDC42 
               
               
                   
               
               
                 11 
                 GLDTVVALL 
                 23203 
                 PMPCA 
               
               
                   
               
               
                 12 
                 GLLLLVPLL 
                 145864 
                 HAPLN3 
               
               
                   
               
               
                 13 
                 HLVPASWKL 
                 3718 
                 JAK3 
               
               
                   
               
               
                 14 
                 LLSDPTPGA 
                 3718 
                 JAK3 
               
               
                   
               
               
                 15 
                 IIIEDLLEA 
                 10985 
                 GCN1L1 
               
               
                   
               
               
                 16 
                 TLIAAILYL 
                 5355 
                 PLP2 
               
               
                   
               
               
                 17 
                 VIIPLLSSV 
                 91526 
                 ANKRD44 
               
               
                   
               
               
                 18 
                 KLTDQPPLV 
                 91526 
                 ANKRD44 
               
               
                   
               
               
                 19 
                 VLEAILPLV 
                 2889 
                 RAPGEF1 
               
               
                   
               
               
                 20 
                 YLIAGGDRWL 
                 2646 
                 GCKR 
               
               
                   
               
               
                 21 
                 ALFKEAYSL 
                 55732 
                 C1orf112 
               
               
                   
               
               
                 22 
                 ALKKHLTSV 
                 10773 
                 ZBTB6 
               
               
                   
               
               
                 23 
                 ALVEDIINL 
                 92399 
                 MRRF 
               
               
                   
               
               
                 24 
                 AVLGFSFRL 
                 80222 
                 TARS2 
               
               
                   
               
               
                 25 
                 FLDTSNQHLL 
                 4064 
                 CD180 
               
               
                   
               
               
                 26 
                 FLGSFIDHV 
                 91147 
                 TMEM67 
               
               
                   
               
               
                 27 
                 FLNQESFDL 
                 6610 
                 SMPD2 
               
               
                   
               
               
                 28 
                 FLSNANPSL 
                 7818 
                 DAP3 
               
               
                   
               
               
                 29 
                 ILSDVTQGL 
                 55591 
                 VEZT 
               
               
                   
               
               
                 30 
                 ILSTLDVEL 
                 10744, 9232 
                 PTTG2, PTTG1 
               
               
                   
               
               
                 31 
                 KLYDEESLL 
                 57680 
                 CHD8 
               
               
                   
               
               
                 32 
                 VLNEDELPSV 
                 57680 
                 CHD8 
               
               
                   
               
               
                 33 
                 LLANIVPIAMLV 
                 4539, 6775071, 
                 MT-ND4L 
               
               
                   
                   
                 8923201 
                   
               
               
                   
               
               
                 34 
                 LLWEDGVTEA 
                 22916 
                 NCBP2 
               
               
                   
               
               
                 35 
                 SLSSERYYL 
                 8320 
                 EOMES 
               
               
                   
               
               
                 36 
                 VILDIPLLFET 
                 79877 
                 DCAKD 
               
               
                   
               
               
                 37 
                 VLGNALEGV 
                 4678 
                 NASP 
               
               
                   
               
               
                 38 
                 YLTAEILELAGN 
                 221613, 3012, 
                 HIST1H2AA, HIST1H2AE, 
               
               
                   
                   
                 3013, 3014, 317772, 
                 HIST1H2AD, H2AFX, 
               
               
                   
                   
                 55766, 723790, 8329, 
                 HIST2H2AB, H2AFJ, 
               
               
                   
                   
                 8330, 8331, 8332, 
                 HIST2H2AA4, HIST1H2A1, 
               
               
                   
                   
                 8334, 8335, 8336, 
                 HIST1H2AK, HIST1H2AJ, 
               
               
                   
                   
                 8337, 8338, 85235, 
                 HIST1H2AL, HIST1H2AC, 
               
               
                   
                   
                 8969, 92815, 9555 
                 HIST1H2AB, HIST1H2AM, 
               
               
                   
                   
                   
                 HIST2H2AA3, HIST2H2AC, 
               
               
                   
                   
                   
                 HIST1H2AH, HIST1H2AG, 
               
               
                   
                   
                   
                 HIST3H2A, H2AFY 
               
               
                   
               
               
                 39 
                 QLLPQGIVPAL 
                 55374 
                 TMCO6 
               
               
                   
               
               
                 40 
                 FLNSVIVDL 
                 6249 
                 CLIP1 
               
               
                   
               
               
                 41 
                 ILASIFETV 
                 6574 
                 SLC20A1 
               
               
                   
               
               
                 42 
                 YLQDLVERA 
                 10347 
                 ABCA7 
               
               
                   
               
               
                 43 
                 ALLEGVKNV 
                 84678 
                 KDM2B 
               
               
                   
               
               
                 44 
                 FIIEEQSFL 
                 10200 
                 MPHOSPH6 
               
               
                   
               
               
                 45 
                 FILDDSALYL 
                 23130 
                 ATG2A 
               
               
                   
               
               
                 46 
                 FLVEEIFQT 
                 8888 
                 MCM3AP 
               
               
                   
               
               
                 47 
                 GLLPKLTAL 
                 22920 
                 KIFAP3 
               
               
                   
               
               
                 48 
                 KILDEDLYI 
                 641 
                 BLM 
               
               
                   
               
               
                 49 
                 TILGDPQILL 
                 23460 
                 ABCA6 
               
               
                   
               
               
                 50 
                 LLLDGLIYL 
                 23460 
                 ABCA6 
               
               
                   
               
               
                 51 
                 SLLGNSPVL 
                 23460 
                 ABCA6 
               
               
                   
               
               
                 52 
                 VLLEDVDAAFL 
                 617 
                 BCS1L 
               
               
                   
               
               
                 53 
                 FLREYFERL 
                 5573 
                 PRKAR1A 
               
               
                   
               
               
                 54 
                 DIFDAMFSV 
                 5573 
                 PRKAR1A 
               
               
                   
               
               
                 55 
                 ILVEVDLVQA 
                 4261 
                 CIITA 
               
               
                   
               
               
                 56 
                 GLQDLLFSL 
                 4261 
                 CIITA 
               
               
                   
               
               
                 57 
                 LQIGDFVSV 
                 51167 
                 CYB5R4 
               
               
                   
               
               
                 58 
                 QLAPFLPQL 
                 23392 
                 KIAA0368 
               
               
                   
               
               
                 59 
                 RLHREVAQV 
                 2802 
                 GOLGA3 
               
               
                   
               
               
                 60 
                 SLLIDVITV 
                 51534 
                 VTA1 
               
               
                   
               
               
                 61 
                 SLLNKDLSL 
                 1786 
                 DNMT1 
               
               
                   
               
               
                 62 
                 ALAPYLDLL 
                 54093 
                 SETD4 
               
               
                   
               
               
                 63 
                 ALIEEAYGL 
                 3836, 3841 
                 KPNA1, KPNA5 
               
               
                   
               
               
                 64 
                 FLVEVSNDV 
                 23224 
                 SYNE2 
               
               
                   
               
               
                 65 
                 NLTDVSPDL 
                 23224 
                 SYNE2 
               
               
                   
               
               
                 66 
                 KLAPIPVEL 
                 153241 
                 CEP120 
               
               
                   
               
               
                 67 
                 LLATVNVAL 
                 23511 
                 NUP188 
               
               
                   
               
               
                 68 
                 QIAAFLFTV 
                 56006 
                 SMG9 
               
               
                   
               
               
                 69 
                 TLLAFPLLL 
                 84720 
                 PIGO 
               
               
                   
               
               
                 70 
                 VLIEILQKA 
                 23633, 3841 
                 KPNA6, KPNA5 
               
               
                   
               
               
                 71 
                 VLLDYVGNVQL 
                 51676 
                 ASB2 
               
               
                   
               
               
                 72 
                 TLQEETAVYL 
                 51676 
                 ASB2 
               
               
                   
               
               
                 73 
                 YLGEEYPEV 
                 23451 
                 SF3B1 
               
               
                   
               
               
                 74 
                 SLDLRPLEV 
                 43 
                 ACHE 
               
               
                   
               
               
                 75 
                 AALKYIPSV 
                 1794 
                 DOCK2 
               
               
                   
               
               
                 76 
                 ALADLVPVDVVV 
                 84188 
                 FAR1 
               
               
                   
               
               
                 77 
                 ALLDVSNNYGI 
                 115752 
                 DIS3L 
               
               
                   
               
               
                 78 
                 AMEEAVAQV 
                 22897 
                 CEP164 
               
               
                   
               
               
                 79 
                 AMKEEKEQL 
                 9126 
                 SMC3 
               
               
                   
               
               
                 80 
                 YLFDEIDQA 
                 9126 
                 SMC3 
               
               
                   
               
               
                 81 
                 FIFSYITAV 
                 128338 
                 DRAM2 
               
               
                   
               
               
                 82 
                 FLIDGSSSV 
                 1690 
                 COCH 
               
               
                   
               
               
                 83 
                 FLMDDNMSNTL 
                 4603 
                 MYBL1 
               
               
                   
               
               
                 84 
                 FLQELQLEHA 
                 8604 
                 SLC25A12 
               
               
                   
               
               
                 85 
                 GLAPAEVVVATVA 
                 57591 
                 MKL1 
               
               
                   
               
               
                 86 
                 GLATIRAYL 
                 2731 
                 GLDC 
               
               
                   
               
               
                 87 
                 GLFARIIMI 
                 5250 
                 SLC25A3 
               
               
                   
               
               
                 88 
                 GLFDNRSGLPEA 
                 79733 
                 E2F8 
               
               
                   
               
               
                 89 
                 GLTALHVAV 
                 602 
                 BCL3 
               
               
                   
               
               
                 90 
                 HLDEVFLEL 
                 55744 
                 COA1 
               
               
                   
               
               
                 91 
                 HLSSTTAQV 
                 201633 
                 TIGIT 
               
               
                   
               
               
                 92 
                 KLLFEIASA 
                 124460 
                 SNX20 
               
               
                   
               
               
                 93 
                 KLLGSLQLL 
                 81603 
                 TRIM8 
               
               
                   
               
               
                 94 
                 LLAGQATTAYF 
                 972 
                 CD74 
               
               
                   
               
               
                 95 
                 LLFDLIPVVSV 
                 284114 
                 TMEM102 
               
               
                   
               
               
                 96 
                 LLLNENESLFL 
                 26156 
                 RSL1D1 
               
               
                   
               
               
                 97 
                 LLNFSPGNL 
                 3929 
                 LBP 
               
               
                   
               
               
                 98 
                 MLQDGIARL 
                 79697 
                 C14orf169 
               
               
                   
               
               
                 99 
                 QLYDGATALFL 
                 147463 
                 AN KRD29 
               
               
                   
               
               
                 100 
                 RLIRTIAAI 
                 140461 
                 ASB8 
               
               
                   
               
               
                 101 
                 SLDQSTWNV 
                 23240 
                 KIAA0922 
               
               
                   
               
               
                 102 
                 SLFAAISGMIL 
                 931 
                 MS4A1 
               
               
                   
               
               
                 103 
                 SLQDHLEKV 
                 1756 
                 DMD 
               
               
                   
               
               
                 104 
                 VLLGLPLLV 
                 9674 
                 KIAA0040 
               
               
                   
               
               
                 105 
                 VLTPVILQV 
                 100499483, 100499484 
                 C9orf174 
               
               
                   
               
               
                 106 
                 VLYELLQYI 
                 51513 
                 ETV7 
               
               
                   
               
               
                 107 
                 VQAVSIPEV 
                 55755 
                 CDK5RAP2 
               
               
                   
               
               
                 108 
                 YLAPENGYLM 
                 6625 
                 SNRNP70 
               
               
                   
               
               
                 109 
                 YLFQFSAAL 
                 130367 
                 SGPP2 
               
               
                   
               
               
                 110 
                 YQYPFVLGL 
                 130367 
                 SGPP2 
               
               
                   
               
               
                 111 
                 YLLDTLLSL 
                 57448 
                 BIRC6 
               
               
                   
               
               
                 112 
                 FLAILPEEV 
                 7762 
                 ZNF215 
               
               
                   
               
               
                 113 
                 FVIDSFEEL 
                 147945 
                 NLRP4 
               
               
                   
               
               
                 114 
                 GLSDISPST 
                 26005 
                 C2CD3 
               
               
                   
               
               
                 115 
                 LLIDIIHFL 
                 25914 
                 RTTN 
               
               
                   
               
               
                 116 
                 SLLDNLLTI 
                 25914 
                 RTTN 
               
               
                   
               
               
                 117 
                 VLATILAQL 
                 26271 
                 FBXO5 
               
               
                   
               
               
                 118 
                 VLDGMIYAI 
                 54813 
                 KLHL28 
               
               
                   
               
               
                 119 
                 ELCDIILRV 
                 54813 
                 KLHL28 
               
               
                   
               
               
                 120 
                 VLLGTTWAL 
                 221188 
                 GPR114 
               
               
                   
               
               
                 121 
                 YLTGYNFTL 
                 9521 
                 EEF1E1 
               
               
                   
               
               
                 122 
                 AISEAQESV 
                 79882 
                 ZC3H14 
               
               
                   
               
               
                 123 
                 ALLSAFVQL 
                 8295 
                 TRRAP 
               
               
                   
               
               
                 124 
                 FLGVVVPTV 
                 56996 
                 SLC12A9 
               
               
                   
               
               
                 125 
                 FVAPPTAAV 
                 162 
                 AP1B1 
               
               
                   
               
               
                 126 
                 GLSIFIYRL 
                 10075 
                 HUWE1 
               
               
                   
               
               
                 127 
                 HLMEENMIVYV 
                 65220 
                 NADK 
               
               
                   
               
               
                 128 
                 KLFDASPTFFA 
                 3992, 3995 
                 FADS1, FADS3 
               
               
                   
               
               
                 129 
                 SLFEASQQL 
                 23347 
                 SMCHD1 
               
               
                   
               
               
                 130 
                 VIFSYVLGV 
                 79004 
                 CUEDC2 
               
               
                   
               
               
                 131 
                 VLIEETDQL 
                 6924 
                 TCEB3 
               
               
                   
               
               
                 132 
                 VLQDQVDEL 
                 51199 
                 NIN 
               
               
                   
               
               
                 133 
                 ALEELTGFREL 
                 4288 
                 MKI67 
               
               
                   
               
               
                 134 
                 ALGRLGILSV 
                 22828, 26230 
                 SCAF8, TIAM2 
               
               
                   
               
               
                 135 
                 ALTGLQFQL 
                 22797 
                 TFEC 
               
               
                   
               
               
                 136 
                 FIFGIVHLL 
                 64066 
                 MMP27 
               
               
                   
               
               
                 137 
                 FIQQERFFL 
                 4012 
                 LNPEP 
               
               
                   
               
               
                 138 
                 NLINNIFEL 
                 4012 
                 LNPEP 
               
               
                   
               
               
                 139 
                 FLASPLVAI 
                 3593 
                 IL12B 
               
               
                   
               
               
                 140 
                 FLFEDFVEV 
                 140775 
                 SMCR8 
               
               
                   
               
               
                 141 
                 FLGELTLQL 
                 257218 
                 SHPRH 
               
               
                   
               
               
                 142 
                 FLYEDSKSVRL 
                 696 
                 BTN1A1 
               
               
                   
               
               
                 143 
                 TLHAVDVTL 
                 696 
                 BTN1A1 
               
               
                   
               
               
                 144 
                 GLITQVDKL 
                 9183 
                 ZW10 
               
               
                   
               
               
                 145 
                 GLLHEVVSL 
                 163486 
                 DENND1B 
               
               
                   
               
               
                 146 
                 GLLQQPPAL 
                 1871 
                 E2F3 
               
               
                   
               
               
                 147 
                 GLSEYQRNFL 
                 56890 
                 MDM1 
               
               
                   
               
               
                 148 
                 ICAGHVPGV 
                 79019 
                 CENPM 
               
               
                   
               
               
                 149 
                 ILNPVTTKL 
                 81691 
                 LOC81691 
               
               
                   
               
               
                 150 
                 ILSEKEYKL 
                 127254 
                 C1orf173 
               
               
                   
               
               
                 151 
                 ILVKQSPML 
                 940 
                 CD28 
               
               
                   
               
               
                 152 
                 KIMYTLVSV 
                 3709 
                 ITPR2 
               
               
                   
               
               
                 153 
                 KLLKGIYAI 
                 1235 
                 CCR6 
               
               
                   
               
               
                 154 
                 KLMNIQQQL 
                 11214 
                 AKAP13 
               
               
                   
               
               
                 155 
                 KLMTSLVKV 
                 10734 
                 STAG3 
               
               
                   
               
               
                 156 
                 KMLEDDLKL 
                 2334 
                 AFF2 
               
               
                   
               
               
                 157 
                 KVLEFLAKV 
                 139422, 4113, 4115 
                 MAGEB10, MAGEB2, 
               
               
                   
                   
                   
                 MAGEB4 
               
               
                   
               
               
                 158 
                 KVQDVLHQV 
                 83756 
                 TAS1R3 
               
               
                   
               
               
                 159 
                 LLLSDSGFYL 
                 28557 
                 TRBV30 
               
               
                   
               
               
                 160 
                 LLPPPSPAA 
                 83881 
                 MIXL1 
               
               
                   
               
               
                 161 
                 NLMLELETV 
                 1063 
                 CENPF 
               
               
                   
               
               
                 162 
                 RLADLKVSI 
                 2175 
                 FANCA 
               
               
                   
               
               
                 163 
                 SIFDAVLKGV 
                 157680 
                 VPS13B 
               
               
                   
               
               
                 164 
                 SLFDGAVISTV 
                 23049 
                 SMG1 
               
               
                   
               
               
                 165 
                 KLLEEIEFL 
                 23049 
                 SMG1 
               
               
                   
               
               
                 166 
                 SLFSEVASL 
                 22832 
                 KIAA1009 
               
               
                   
               
               
                 167 
                 SLFSITKSV 
                 60468 
                 BACH2 
               
               
                   
               
               
                 168 
                 SLLSPLLSV 
                 54949 
                 SDHAF2 
               
               
                   
               
               
                 169 
                 SSLEENLLHQV 
                 80205 
                 CHD9 
               
               
                   
               
               
                 170 
                 STIELSENSL 
                 55635 
                 DEPDC1 
               
               
                   
               
               
                 171 
                 TLLDVISAL 
                 27340 
                 UTP20 
               
               
                   
               
               
                 172 
                 TLQDSLEFI 
                 51735, 96459 
                 RAPGEF6, FNIP1 
               
               
                   
               
               
                 173 
                 VILDSVASV 
                 5890 
                 RAD51B 
               
               
                   
               
               
                 174 
                 VLVEITDVDFAA 
                 79801 
                 SHCBP1 
               
               
                   
               
               
                 175 
                 VMESILLRL 
                 342850 
                 ANKRD62 
               
               
                   
               
               
                 176 
                 YLHIYESQL 
                 29851 
                 ICOS 
               
               
                   
               
               
                 177 
                 YLYEAEEATTL 
                 22798 
                 LAMB4 
               
               
                   
               
               
                 178 
                 YVLQGEFFL 
                 84541 
                 KBTBD8 
               
               
                   
               
               
                 179 
                 FVDTNLYFL 
                 81037 
                 CLPTM1L 
               
               
                   
               
               
                 180 
                 GILQLVESV 
                 6050 
                 RNH1 
               
               
                   
               
               
                 181 
                 LLFDQNDKV 
                 100653071, 10491 
                 CRTAP 
               
               
                   
               
               
                 182 
                 LLPPPPPVA 
                 23091, 4784 
                 ZC3H13, NFIX 
               
               
                   
               
               
                 183 
                 VLFETVLTI 
                 8906 
                 AP1G2 
               
               
                   
               
               
                 184 
                 AVLGTSWQL 
                 23041 
                 MON2 
               
               
                   
               
               
                 185 
                 FIAQLNNVEL 
                 6509 
                 SLC1A4 
               
               
                   
               
               
                 186 
                 FLDVSRDFV 
                 54461 
                 FBXW5 
               
               
                   
               
               
                 187 
                 FLNSFVFKM 
                 89910 
                 UBE3B 
               
               
                   
               
               
                 188 
                 GLEDEMYEV 
                 285905, 644619, 
                 INTS4L1, INTS4L2, INTS4 
               
               
                   
                   
                 92105 
                   
               
               
                   
               
               
                 189 
                 SLSHLVPAL 
                 285905, 644619, 
                 INTS4L1, INTS4L2, INTS4 
               
               
                   
                   
                 92105 
                   
               
               
                   
               
               
                 190 
                 GLIELVDQL 
                 90410 
                 IFT20 
               
               
                   
               
               
                 191 
                 GLSDISAQV 
                 5989 
                 RFX1 
               
               
                   
               
               
                 192 
                 GMAAEVPKV 
                 348378 
                 FAM159A 
               
               
                   
               
               
                 193 
                 SLADSMPSL 
                 8945 
                 BTRC 
               
               
                   
               
               
                 194 
                 SLAPFDREPFTL 
                 3937 
                 LCP2 
               
               
                   
               
               
                 195 
                 ALIPDLNQI 
                 51361 
                 HOOK1 
               
               
                   
               
               
                 196 
                 TLALAMIYL 
                 100134301, 285074, 
                 ANAPC1 
               
               
                   
                   
                 64682, 730268 
                   
               
               
                   
               
               
                 197 
                 YLLTDNVVKL 
                 79810 
                 PTCD2 
               
               
                   
               
               
                 198 
                 GLLSAVSSV 
                 9894 
                 TELO2 
               
               
                   
               
               
                 199 
                 SLNSTTWKV 
                 1233 
                 CCR4 
               
               
                   
               
               
                 200 
                 YLLDFEDRL 
                 23207 
                 PLEKHM2 
               
               
                   
               
               
                 201 
                 YLNISQVNV 
                 9262 
                 STK17B 
               
               
                   
               
               
                 202 
                 ALAAGGYDV 
                 3009 
                 HIST1H1B 
               
               
                   
               
               
                 203 
                 ILDTIFHKV 
                 2829 
                 XCR1 
               
               
                   
               
               
                 204 
                 RLCDIVVNV 
                 84614 
                 ZBTB37 
               
               
                   
               
               
                 205 
                 TLFYESPHL 
                 221908 
                 PPP1R35 
               
               
                   
               
               
                 206 
                 SAVSGQWEV 
                 2326 
                 FMO1 
               
               
                   
               
               
                 207 
                 GLVGLLEQA 
                 57572, 81704, 85440 
                 DOCK6, DOCK8, DOCK7 
               
               
                   
               
               
                 208 
                 FLAVSLPLL 
                 3071 
                 NCKAP1L 
               
               
                   
               
               
                 209 
                 FLLDTISGL 
                 84864 
                 MINA 
               
               
                   
               
               
                 210 
                 FLAEQFEFL 
                 55610 
                 CCDC132 
               
               
                   
               
               
                 211 
                 FIDDLFAFV 
                 1209 
                 CLPTM1 
               
               
                   
               
               
                 212 
                 FLIGQGAHV 
                 4659 
                 PPP1R12A 
               
               
                   
               
               
                 213 
                 YINEDEYEV 
                 7874 
                 USP7 
               
               
                   
               
               
                 214 
                 FLFDGSMSL 
                 3683 
                 ITGAL 
               
               
                   
               
               
                 215 
                 QLFEEEIEL 
                 63906 
                 GPATCH3 
               
               
                   
               
               
                 216 
                 KVVSNLPAI 
                 10199 
                 MPHOSPH10 
               
               
                   
               
               
                 217 
                 AQFGAVLEV 
                 55131 
                 RBM28 
               
               
                   
               
               
                 218 
                 ALDQFLEGI 
                 57169 
                 ZNFX1 
               
               
                   
               
               
                 219 
                 ALLELENSV 
                 715, 83481 
                 C1R, EPPK1 
               
               
                   
               
               
                 220 
                 FLAEAPTAL 
                 9814 
                 SFI1 
               
               
                   
               
               
                 221 
                 FLAPDNSLLLA 
                 22898 
                 DENND3 
               
               
                   
               
               
                 222 
                 FLIETGTLL 
                 79705 
                 LRRK1 
               
               
                   
               
               
                 223 
                 FLQDIPDGLFL 
                 206426, 266971, 
                 PIP5K1P1, PIPSL, PIP5K1A 
               
               
                   
                   
                 8394 
                   
               
               
                   
               
               
                 224 
                 FLSPLLPLL 
                 10961 
                 ERP29 
               
               
                   
               
               
                 225 
                 GTYQDVGSLNIGDV 
                 973 
                 CD79A 
               
               
                   
               
               
                 226 
                 GVIDPVPEV 
                 8879 
                 SGPL1 
               
               
                   
               
               
                 227 
                 IIAEGIPEA 
                 47 
                 ACLY 
               
               
                   
               
               
                 228 
                 IIAEYLSYV 
                 51667 
                 NUB1 
               
               
                   
               
               
                 229 
                 ILSPWGAEV 
                 142 
                 PARP1 
               
               
                   
               
               
                 230 
                 IMDDDSYGV 
                 9874 
                 TLK1 
               
               
                   
               
               
                 231 
                 IVMGAIPSV 
                 1902 
                 LPAR1 
               
               
                   
               
               
                 232 
                 KVMEGTVAA 
                 1445 
                 CSK 
               
               
                   
               
               
                 233 
                 MLEVHIPSV 
                 79856 
                 SNX22 
               
               
                   
               
               
                 234 
                 NLQRTVVTV 
                 4297 
                 MLL 
               
               
                   
               
               
                 235 
                 SLDVYELFL 
                 79586 
                 CHPF 
               
               
                   
               
               
                 236 
                 SLFDGFFLTA 
                 25920 
                 COBRA1 
               
               
                   
               
               
                 237 
                 YLDRLIPQA 
                 115209 
                 OMA1 
               
               
                   
               
               
                 238 
                 YQYGAVVTL 
                 1380 
                 CR2 
               
               
                   
               
               
                 239 
                 VLIDDTVLL 
                 116138 
                 KLHDC3 
               
               
                   
               
               
                 240 
                 ALVPTPALFYL 
                 51528 
                 JKAMP 
               
               
                   
               
               
                 241 
                 FIPDFIPAV 
                 56912 
                 IFT46 
               
               
                   
               
               
                 242 
                 GILDFZVFL 
                 100124692, 8972, 
                 MGAM 
               
               
                   
                   
                 93432 
                   
               
               
                   
               
               
                 243 
                 GLPDLDIYL 
                 23334 
                 SZT2 
               
               
                   
               
               
                 244 
                 ILEPFLPAV 
                 6894 
                 TARBP1 
               
               
                   
               
               
                 245 
                 KLIQLPVVYV 
                 9875 
                 URB1 
               
               
                   
               
               
                 246 
                 KLPVPLESV 
                 285190, 400966, 5903, 
                 RGPD4, RGPD1, RANBP2, 
               
               
                   
                   
                 653489, 727851, 
                 RGPD3, RGPD8, RGPD6, 
               
               
                   
                   
                 729540, 729857, 84220 
                 RGPD2, RGPD5 
               
               
                   
               
               
                 247 
                 KVLEMETTV 
                 9810 
                 RNF40 
               
               
                   
               
               
                 248 
                 NLLEQFILL 
                 64708 
                 COPS7B 
               
               
                   
               
               
                 249 
                 VLLESLVEI 
                 149371 
                 EXOC8 
               
               
                   
               
               
                 250 
                 VLTNVGAAL 
                 129285 
                 PPP1R21 
               
               
                   
               
               
                 251 
                 VLYELFTYI 
                 3717 
                 JAK2 
               
               
                   
               
               
                 252 
                 YLGDLIMAL 
                 3930, 7108 
                 LBR, TM7SF2 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Additional peptides according to the present invention with no 
               
               
                 prior known cancer association. 
               
             
          
           
               
                 SEQ ID 
                   
                   
                   
               
               
                 No. 
                 Sequence 
                 GeneID(s) 
                 Official Gene Symbol(s) 
               
               
                   
               
               
                 253 
                 YSDDDVPSV 
                 29028 
                 ATAD2 
               
               
                   
               
               
                 254 
                 FLYSETWNI 
                 4519, 8923205 
                 MT-CYB 
               
               
                   
               
               
                 255 
                 GMWNPNAPVFL 
                 9910 
                 RABGAP1L 
               
               
                   
               
               
                 256 
                 ALQETPPQV 
                 146206 
                 RLTPR 
               
               
                   
               
               
                 257 
                 FLQEWEVYA 
                 57001 
                 ACN9 
               
               
                   
               
               
                 258 
                 RIYPFLLMV 
                 10299 
                 MARCH6 
               
               
                   
               
               
                 259 
                 TVLDGLEFKV 
                 10592 
                 SMC2 
               
               
                   
               
               
                 260 
                 RLDEAFDFV 
                 1844 
                 DUSP2 
               
               
                   
               
               
                 261 
                 FLPETRIMTSV 
                 11319 
                 ECD 
               
               
                   
               
               
                 262 
                 LMGPVVHEV 
                 5116 
                 PCNT 
               
               
                   
               
               
                 263 
                 GLMDNEIKV 
                 8795 
                 TNFRSF10B 
               
               
                   
               
               
                 264 
                 ILTGTPPGV 
                 151313, 51011 
                 FAHD2B, FAHD2A 
               
               
                   
               
               
                 265 
                 ILWHFVASL 
                 23077 
                 MYCBP2 
               
               
                   
               
               
                 266 
                 QLTEMLPSI 
                 689 
                 BTF3 
               
               
                   
               
               
                 267 
                 SLLETGSDLLL 
                 57176 
                 VARS2 
               
               
                   
               
               
                 268 
                 VLFPLPTPL 
                 11184 
                 MAP4K1 
               
               
                   
               
               
                 269 
                 VLQNVAFSV 
                 597 
                 BCL2A1 
               
               
                   
               
               
                 270 
                 VVVDSDSLAFV 
                 122961 
                 ISCA2 
               
               
                   
               
               
                 271 
                 YLLDQPVLEQRL 
                 81887 
                 LAS1L 
               
               
                   
               
               
                 272 
                 KLDHTLSQI 
                 4863 
                 NPAT 
               
               
                   
               
               
                 273 
                 AILLPQPPK 
                 1761, 6392, 64147, 
                 DMRT1, SDHD, KIF9, 
               
               
                   
                   
                 642204, 654434, 
                 LINC00338, TMEM175, 
               
               
                   
                   
                 84286, 85363 
                 TRIMS 
               
               
                   
               
               
                 274 
                 KLLNLISKL 
                 5366 
                 PMAIP1 
               
               
                   
               
               
                 275 
                 KLMDLEDCAL 
                 23269 
                 MGA 
               
               
                   
               
               
                 276 
                 NMISYVVHL 
                 204801 
                 NLRP11 
               
               
                   
               
               
                 277 
                 FLIDLNSTHGTFL 
                 5511 
                 PPP1R8 
               
               
                   
               
               
                 278 
                 FLLFINHRL 
                 4292 
                 MLH1 
               
               
                   
               
               
                 279 
                 NLAGENILNPL 
                 56948 
                 SDR39U1 
               
               
                   
               
               
                 280 
                 SLLNHLPYL 
                 201562 
                 PTPLB 
               
               
                   
               
               
                 281 
                 TLQTVPLTTV 
                 1997 
                 ELF1 
               
               
                   
               
               
                 282 
                 YLLEQGAQV 
                 55527 
                 FEM1A 
               
               
                   
               
               
                 283 
                 ALMPVTPQA 
                 23683 
                 PRKD3 
               
               
                   
               
               
                 284 
                 KLQEQIHRV 
                 196441 
                 ZFC3H1 
               
               
                   
               
               
                 285 
                 SITAVTPLL 
                 63910 
                 SLC17A9 
               
               
                   
               
               
                 286 
                 HLTEDTPKV 
                 50814 
                 NSDHL 
               
               
                   
               
               
                 287 
                 ILMGHSLYM 
                 9786 
                 KIAA0586 
               
               
                   
               
               
                 288 
                 RLAPEIVSA 
                 157285 
                 SGK223 
               
               
                   
               
               
                 289 
                 SLLAANNLL 
                 9380 
                 GRHPR 
               
               
                   
               
               
                 290 
                 IASPVIAAV 
                 127544 
                 RNF19B 
               
               
                   
               
               
                 291 
                 KIIDTAGLSEA 
                 22954 
                 TRIM32 
               
               
                   
               
               
                 292 
                 KLINSQISL 
                 5293 
                 PIK3CD 
               
               
                   
               
               
                 293 
                 GLAMVEAISYV 
                 109 
                 ADCY3 
               
               
                   
               
               
                 294 
                 KLYGPEGLELV 
                 3394 
                 IRF8 
               
               
                   
               
               
                 295 
                 SLAAVSQQL 
                 7094 
                 TLN1 
               
               
                   
               
               
                 296 
                 FILEPLYKI 
                 9343 
                 EFTUD2 
               
               
                   
               
               
                 297 
                 ILQNGLETL 
                 89857 
                 KLHL6 
               
               
                   
               
               
                 298 
                 ALTDVILCV 
                 89857 
                 KLHL6 
               
               
                   
               
               
                 299 
                 RLLEEEGVSL 
                 64428 
                 NARFL 
               
               
                   
               
               
                 300 
                 IVLERNPEL 
                 5257 
                 PHKB 
               
               
                   
               
               
                 301 
                 LQFDGIHVV 
                 55294 
                 FBXW7 
               
               
                   
               
               
                 302 
                 SLAELDEKISA 
                 51562 
                 MBIP 
               
               
                   
               
               
                 303 
                 FVWEASHYL 
                 5442 
                 POLRMT 
               
               
                   
               
               
                 304 
                 ALIRLDDLFL 
                 56902 
                 PNO1 
               
               
                   
               
               
                 305 
                 AMLAQQMQL 
                 4154 
                 MBNL1 
               
               
                   
               
               
                 306 
                 AQVALVNEV 
                 10075 
                 HUWE1 
               
               
                   
               
               
                 307 
                 FLLPVAVKL 
                 3954 
                 LETM1 
               
               
                   
               
               
                 308 
                 SLLDQIPEM 
                 9632 
                 SEC24C 
               
               
                   
               
               
                 309 
                 SLSFVSPSL 
                 11108 
                 PRDM4 
               
               
                   
               
               
                 310 
                 VMAEAPPGV 
                 9798 
                 IST1 
               
               
                   
               
               
                 311 
                 YLHRQVAAV 
                 6890 
                 TAP1 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Peptides useful for e.g. personalized cancer 
               
               
                 therapies. 
               
             
          
           
               
                 SEQ  
                   
                   
                 Official 
               
               
                 ID 
                   
                   
                 Gene 
               
               
                 No. 
                 Sequence 
                 GeneID(s) 
                 Symbol(s) 
               
               
                   
               
               
                 312 
                 RLPDIPLRQV 
                 55656 
                 INT58 
               
               
                   
               
               
                 313 
                 ALSVRISNV 
                 3766 
                 KCNJ10 
               
               
                   
               
               
                 314 
                 LIDDKGTIKL 
                 983 
                 CDK1 
               
               
                   
               
               
                 315 
                 SLYDSIAFI 
                 56978 
                 PRDM8 
               
               
                   
               
               
                 316 
                 SLSAFLPSL 
                 54757 
                 FAM20A 
               
               
                   
               
               
                 317 
                 GLSNLGIKSI 
                 122553 
                 TRAPPC6B 
               
               
                   
               
               
                 318 
                 KIQEMQHFL 
                 4321 
                 MMP12 
               
               
                   
               
               
                 319 
                 SLYKGLLSV 
                 25788 
                 RAD54B 
               
               
                   
               
               
                 320 
                 LLWGNLPEI 
                 729533, 653820 
                 FAM72A, FAM72B 
               
               
                   
               
               
                 321 
                 KLLAVIHEL 
                 25788 
                 RAD54B 
               
               
                   
               
               
                 322 
                 TLTNIIHNL 
                 94101 
                 ORMDL1 
               
               
                   
               
               
                 323 
                 ILVDWLVQV 
                 9133 
                 CCNB2 
               
               
                   
               
               
                 324 
                 LLYDAVHIV 
                 2899 
                 GRIK3 
               
               
                   
               
               
                 325 
                 FLFVDPELV 
                 146850 
                 PIK3R6 
               
               
                   
               
               
                 326 
                 KLTDVGIATL 
                 115701 
                 ALPK2 
               
               
                   
               
               
                 327 
                 MLFGHPLLVSV 
                 8237 
                 USP11 
               
               
                   
               
               
                 328 
                 ILFPDIIARA 
                 64110 
                 MAGEF1 
               
               
                   
               
             
          
         
       
     
         [0057]    The present invention furthermore generally relates to the peptides according to the present invention for use in the treatment of proliferative diseases, such as, for example, non-small cell lung cancer, small cell lung cancer, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanoma, ovarian cancer, urinary bladder cancer, uterine cancer, gallbladder and bile duct cancer. 
         [0058]    Particularly preferred are the peptides—alone or in combination—according to the present invention selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 311. More preferred are the peptides—alone or in combination—selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 217 (see Table 1), and their uses in the immunotherapy of NHL, non-small cell lung cancer, small cell lung cancer, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanoma, ovarian cancer, urinary bladder cancer, uterine cancer, gallbladder and bile duct cancer, and preferably NHL. 
         [0059]    As shown in the following Tables 4A and B, many of the peptides according to the present invention are also found on other tumor types and can, thus, also be used in the immunotherapy of other indications. Also, refer to  FIGS. 1A-1P  and Example 1. 
         [0060]    The tables show for selected peptides on which additional tumor types they were found and either over-presented on more than 5% of the measured tumor samples, or presented on more than 5% of the measured tumor samples with a ratio of geometric means tumor vs normal tissues being larger than 3. Over-presentation is defined as higher presentation on the tumor sample as compared to the normal sample with highest presentation. Normal tissues against which over-presentation was tested were: adipose tissue, adrenal gland, artery, bone marrow, brain, central nerve, colon, duodenum, esophagus, eye, gallbladder, heart, kidney, liver, lung, lymph node, mononuclear white blood cells, pancreas, peripheral nerve, parathyroid gland, peritoneum, pituitary, pleura, rectum, salivary gland, skeletal muscle, skin, small intestine, spleen, stomach, thymus, thyroid gland, trachea, ureter, urinary bladder, and vein. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 4A 
               
             
             
               
                   
               
               
                 Peptides according to the present invention and their specific uses in 
               
               
                 other proliferative diseases, especially in other cancerous diseases. 
               
             
          
           
               
                 SEQ ID No. 
                 Sequence 
                 Other relevant organs/diseases 
               
               
                   
               
             
          
           
               
                 1 
                 LLSGQLPTI 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 2 
                 LLSEETPSA 
                 NSCLC, SCLC, CLL, AML, BRCA, 
               
               
                   
                   
                 Melanoma, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 3 
                 LTIDTQYYL 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 5 
                 VLQGLTFTL 
                 SCLC, CLL, BRCA, Melanoma, OC, 
               
               
                   
                   
                 Urinary bladder cancer, Uterine Cancer, 
               
               
                   
                   
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 6 
                 TLITLPLLFL 
                 CLL, Melanoma 
               
               
                   
               
               
                 7 
                 NLLGMIFSM 
                 CLL, AML, Melanoma, Urinary bladder 
               
               
                   
                   
                 cancer 
               
               
                   
               
               
                 8 
                 ALYAVIEKA 
                 CLL, AML 
               
               
                   
               
               
                 9 
                 FLLDLDPLL 
                 CLL 
               
               
                   
               
               
                 10 
                 FLLVGTQIDL 
                 CLL, BRCA, Uterine Cancer 
               
               
                   
               
               
                 11 
                 GLDTVVALL 
                 CRC, CLL, AML, BRCA, Uterine Cancer 
               
               
                   
               
               
                 12 
                 GLLLLVPLL 
                 Melanoma, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 13 
                 HLVPASWKL 
                 CLL, Melanoma 
               
               
                   
               
               
                 15 
                 IIIEDLLEA 
                 BRCA, Melanoma, Uterine Cancer 
               
               
                   
               
               
                 16 
                 TLIAAILYL 
                 CLL, AML, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 17 
                 VIIPLLSSV 
                 CLL, AML, BRCA, Melanoma 
               
               
                   
               
               
                 19 
                 VLEAILPLV 
                 CLL 
               
               
                   
               
               
                 20 
                 YLIAGGDRWL 
                 NSCLC, RCC, CLL, BRCA, Melanoma 
               
               
                   
               
               
                 21 
                 ALFKEAYSL 
                 Esophageal Cancer 
               
               
                   
               
               
                 23 
                 ALVEDIINL 
                 CRC, BRCA, Melanoma, Uterine Cancer 
               
               
                   
               
               
                 24 
                 AVLGFSFRL 
                 CLL 
               
               
                   
               
               
                 25 
                 FLDTSNQHLL 
                 CLL 
               
               
                   
               
               
                 26 
                 FLGSFIDHV 
                 Melanoma, OC, Uterine Cancer 
               
               
                   
               
               
                 27 
                 FLNQESFDL 
                 CLL, BRCA, Esophageal Cancer, Urinary 
               
               
                   
                   
                 bladder cancer, Uterine Cancer 
               
               
                   
               
               
                 28 
                 FLSNANPSL 
                 CLL, BRCA, Uterine Cancer 
               
               
                   
               
               
                 29 
                 ILSDVTQGL 
                 CLL, BRCA, Uterine Cancer 
               
               
                   
               
               
                 30 
                 ILSTLDVEL 
                 CRC, Melanoma, Uterine Cancer 
               
               
                   
               
               
                 31 
                 KLYDEESLL 
                 CLL, AML, Melanoma, Esophageal 
               
               
                   
                   
                 Cancer, Uterine Cancer 
               
               
                   
               
               
                 32 
                 VLNEDELPSV 
                 CLL 
               
               
                   
               
               
                 33 
                 LLANIVPIAMLV 
                 CLL 
               
               
                   
               
               
                 34 
                 LLWEDGVTEA 
                 CRC, CLL, Melanoma, Esophageal 
               
               
                   
                   
                 Cancer, Urinary bladder cancer, Uterine 
               
               
                   
                   
                 Cancer, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 35 
                 SLSSERYYL 
                 OC 
               
               
                   
               
               
                 36 
                 VILDIPLLFET 
                 CLL, BRCA, Melanoma, Uterine Cancer 
               
               
                   
               
               
                 37 
                 VLGNALEGV 
                 HCC, CLL, AML, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 38 
                 YLTAEILELAGN 
                 NSCLC, SCLC, CRC, HCC, BRCA, 
               
               
                   
                   
                 Melanoma, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer, Gallbladder Cancer, Bile 
               
               
                   
                   
                 Duct Cancer 
               
               
                   
               
               
                 39 
                 QLLPQGIVPAL 
                 CLL, BRCA, OC, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 40 
                 FLNSVIVDL 
                 CLL, Melanoma, Urinary bladder cancer 
               
               
                   
               
               
                 41 
                 ILASIFETV 
                 NSCLC, SCLC, RCC, CLL, AML, BRCA, 
               
               
                   
                   
                 Melanoma, Urinary bladder cancer, 
               
               
                   
                   
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 42 
                 YLQDLVERA 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 43 
                 ALLEGVKNV 
                 CLL, Melanoma, OC 
               
               
                   
               
               
                 44 
                 FIIEEQSFL 
                 CLL, Esophageal Cancer, Gallbladder 
               
               
                   
                   
                 Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 45 
                 FILDDSALYL 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 46 
                 FLVEEIFQT 
                 SCLC, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 47 
                 GLLPKLTAL 
                 RCC, Brain Cancer, CRC, HCC, AML, 
               
               
                   
                   
                 Melanoma, Esophageal Cancer, OC, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 48 
                 KILDEDLYI 
                 CLL, BRCA, Melanoma, Esophageal 
               
               
                   
                   
                 Cancer, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 50 
                 LLLDGLIYL 
                 CLL 
               
               
                   
               
               
                 53 
                 FLREYFERL 
                 CLL, Melanoma, Uterine Cancer 
               
               
                   
               
               
                 55 
                 ILVEVDLVQA 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 56 
                 GLQDLLFSL 
                 CLL, AML 
               
               
                   
               
               
                 57 
                 LQIGDFVSV 
                 SCLC, CLL 
               
               
                   
               
               
                 58 
                 QLAPFLPQL 
                 OC, Urinary bladder cancer 
               
               
                   
               
               
                 59 
                 RLHREVAQV 
                 Esophageal Cancer 
               
               
                   
               
               
                 60 
                 SLLIDVITV 
                 CLL, Melanoma, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 61 
                 SLLNKDLSL 
                 Uterine Cancer 
               
               
                   
               
               
                 62 
                 ALAPYLDLL 
                 AML, Melanoma, Urinary bladder cancer 
               
               
                   
               
               
                 63 
                 ALIEEAYGL 
                 CLL 
               
               
                   
               
               
                 64 
                 FLVEVSNDV 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 65 
                 NLTDVSPDL 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 67 
                 LLATVNVAL 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 68 
                 QIAAFLFTV 
                 CLL, Urinary bladder cancer, Uterine 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 69 
                 TLLAFPLLL 
                 HCC, CLL, AML, Melanoma, Gallbladder 
               
               
                   
                   
                 Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 70 
                 VLIEILQKA 
                 AML, BRCA, OC, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 73 
                 YLGEEYPEV 
                 SCLC, CRC, CLL, Melanoma, Uterine 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 74 
                 SLDLRPLEV 
                 RCC, GC 
               
               
                   
               
               
                 76 
                 ALADLVPVDVVV 
                 SCLC, CLL, BRCA, Melanoma, Uterine 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 77 
                 ALLDVSNNYGI 
                 HCC, CLL, Esophageal Cancer, OC, 
               
               
                   
                   
                 Urinary bladder cancer 
               
               
                   
               
               
                 78 
                 AMEEAVAQV 
                 RCC, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 79 
                 AMKEEKEQL 
                 AML 
               
               
                   
               
               
                 80 
                 YLFDEIDQA 
                 CLL, AML, Uterine Cancer 
               
               
                   
               
               
                 81 
                 FIFSYITAV 
                 CLL 
               
               
                   
               
               
                 82 
                 FLIDGSSSV 
                 CLL 
               
               
                   
               
               
                 83 
                 FLMDDNMSNTL 
                 Melanoma 
               
               
                   
               
               
                 84 
                 FLQELQLEHA 
                 CLL 
               
               
                   
               
               
                 85 
                 GLAPAEVVVATVA 
                 CLL, Melanoma 
               
               
                   
               
               
                 86 
                 GLATIRAYL 
                 RCC, Melanoma, Uterine Cancer 
               
               
                   
               
               
                 87 
                 GLFARIIMI 
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 88 
                 GLFDNRSGLPEA 
                 Urinary bladder cancer, Uterine Cancer 
               
               
                   
               
               
                 90 
                 HLDEVFLEL 
                 SCLC 
               
               
                   
               
               
                 92 
                 KLLFEIASA 
                 CLL, AML 
               
               
                   
               
               
                 93 
                 KLLGSLQLL 
                 RCC, BRCA 
               
               
                   
               
               
                 94 
                 LLAGQATTAYF 
                 RCC 
               
               
                   
               
               
                 95 
                 LLFDLIPVVSV 
                 AML, BRCA, Uterine Cancer 
               
               
                   
               
               
                 96 
                 LLLNENESLFL 
                 HCC, CLL, BRCA, Melanoma, OC, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 97 
                 LLNFSPGNL 
                 CRC 
               
               
                   
               
               
                 98 
                 MLQDGIARL 
                 CLL, Melanoma 
               
               
                   
               
               
                 100 
                 RLIRTIAAI 
                 RCC 
               
               
                   
               
               
                 101 
                 SLDQSTWNV 
                 CLL 
               
               
                   
               
               
                 102 
                 SLFAAISGMIL 
                 CLL 
               
               
                   
               
               
                 103 
                 SLQDHLEKV 
                 HCC, CLL 
               
               
                   
               
               
                 104 
                 VLLGLPLLV 
                 CLL, AML 
               
               
                   
               
               
                 105 
                 VLTPVILQV 
                 CLL, AML 
               
               
                   
               
               
                 106 
                 VLYELLQYI 
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 108 
                 YLAPENGYLM 
                 SCLC, CRC, HCC, BRCA, Melanoma, 
               
               
                   
                   
                 OC, Urinary bladder cancer, Gallbladder 
               
               
                   
                   
                 Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 109 
                 YLFQFSAAL 
                 RCC, PC 
               
               
                   
               
               
                 110 
                 YQYPFVLGL 
                 Uterine Cancer 
               
               
                   
               
               
                 114 
                 GLSDISPST 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 116 
                 SLLDNLLTI 
                 HCC, CLL, AML, Melanoma 
               
               
                   
               
               
                 117 
                 VLATILAQL 
                 SCLC, AML, Uterine Cancer 
               
               
                   
               
               
                 118 
                 VLDGMIYAI 
                 Uterine Cancer 
               
               
                   
               
               
                 119 
                 ELCDIILRV 
                 Melanoma 
               
               
                   
               
               
                 120 
                 VLLGTTWAL 
                 AML 
               
               
                   
               
               
                 121 
                 YLTGYNFTL 
                 Uterine Cancer 
               
               
                   
               
               
                 122 
                 AISEAQESV 
                 RCC, CLL, BRCA, Uterine Cancer 
               
               
                   
               
               
                 124 
                 FLGVVVPTV 
                 CLL, Melanoma, OC, Uterine Cancer 
               
               
                   
               
               
                 125 
                 FVAPPTAAV 
                 Melanoma, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 126 
                 GLSIFIYRL 
                 Melanoma, Urinary bladder cancer 
               
               
                   
               
               
                 127 
                 HLMEENMIVYV 
                 Melanoma 
               
               
                   
               
               
                 128 
                 KLFDASPTFFA 
                 CLL, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 129 
                 SLFEASQQL 
                 CLL, Melanoma, Uterine Cancer, 
               
               
                   
                   
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 130 
                 VIFSYVLGV 
                 AML, Uterine Cancer 
               
               
                   
               
               
                 131 
                 VLIEETDQL 
                 CLL, Melanoma 
               
               
                   
               
               
                 132 
                 VLQDQVDEL 
                 CLL, AML, Melanoma 
               
               
                   
               
               
                 133 
                 ALEELTGFREL 
                 Esophageal Cancer 
               
               
                   
               
               
                 138 
                 NLINNIFEL 
                 CLL, AML, Urinary bladder cancer 
               
               
                   
               
               
                 141 
                 FLGELTLQL 
                 Melanoma 
               
               
                   
               
               
                 144 
                 GLITQVDKL 
                 AML 
               
               
                   
               
               
                 146 
                 GLLQQPPAL 
                 AML 
               
               
                   
               
               
                 148 
                 ICAGHVPGV 
                 AML, Uterine Cancer 
               
               
                   
               
               
                 149 
                 ILNPVTTKL 
                 AML 
               
               
                   
               
               
                 152 
                 KIMYTLVSV 
                 HCC 
               
               
                   
               
               
                 161 
                 NLMLELETV 
                 Uterine Cancer 
               
               
                   
               
               
                 163 
                 SIFDAVLKGV 
                 RCC, CRC, BRCA, Uterine Cancer 
               
               
                   
               
               
                 164 
                 SLFDGAVISTV 
                 SCLC, Uterine Cancer 
               
               
                   
               
               
                 165 
                 KLLEEIEFL 
                 RCC, AML, BRCA, Melanoma, 
               
               
                   
                   
                 Esophageal Cancer, Gallbladder Cancer, 
               
               
                   
                   
                 Bile Duct Cancer 
               
               
                   
               
               
                 166 
                 SLFSEVASL 
                 Melanoma 
               
               
                   
               
               
                 169 
                 SSLEENLLHQV 
                 HCC, CLL 
               
               
                   
               
               
                 171 
                 TLLDVISAL 
                 AML 
               
               
                   
               
               
                 174 
                 VLVEITDVDFAA 
                 Melanoma 
               
               
                   
               
               
                 179 
                 FVDTNLYFL 
                 RCC, CLL, Melanoma, Uterine Cancer 
               
               
                   
               
               
                 180 
                 GILQLVESV 
                 HCC, CLL, AML, Melanoma, OC 
               
               
                   
               
               
                 181 
                 LLFDQNDKV 
                 RCC, HCC, BRCA, Melanoma, Urinary 
               
               
                   
                   
                 bladder cancer, Uterine Cancer 
               
               
                   
               
               
                 182 
                 LLPPPPPVA 
                 SCLC, CLL, Melanoma 
               
               
                   
               
               
                 183 
                 VLFETVLTI 
                 CLL, AML, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 184 
                 AVLGTSWQL 
                 CRC, CLL, AML 
               
               
                   
               
               
                 185 
                 FIAQLNNVEL 
                 Melanoma, OC 
               
               
                   
               
               
                 186 
                 FLDVSRDFV 
                 SCLC, CLL 
               
               
                   
               
               
                 188 
                 GLEDEMYEV 
                 CLL, Melanoma, Uterine Cancer, 
               
               
                   
                   
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 189 
                 SLSHLVPAL 
                 CLL 
               
               
                   
               
               
                 190 
                 GLIELVDQL 
                 HCC, CLL, AML, Melanoma, Uterine 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 191 
                 GLSDISAQV 
                 CLL, Melanoma, Esophageal Cancer, OC 
               
               
                   
               
               
                 193 
                 SLADSMPSL 
                 BRCA, Uterine Cancer 
               
               
                   
               
               
                 194 
                 SLAPFDREPFTL 
                 NSCLC 
               
               
                   
               
               
                 195 
                 ALIPDLNQI 
                 Uterine Cancer 
               
               
                   
               
               
                 197 
                 YLLTDNVVKL 
                 RCC, BRCA 
               
               
                   
               
               
                 198 
                 GLLSAVSSV 
                 AML, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 200 
                 YLLDFEDRL 
                 CLL 
               
               
                   
               
               
                 201 
                 YLNISQVNV 
                 CLL 
               
               
                   
               
               
                 203 
                 ILDTIFHKV 
                 Melanoma 
               
               
                   
               
               
                 204 
                 RLCDIVVNV 
                 Melanoma 
               
               
                   
               
               
                 206 
                 SAVSGQWEV 
                 CLL 
               
               
                   
               
               
                 207 
                 GLVGLLEQA 
                 SCLC, HCC, CLL, AML, BRCA, 
               
               
                   
                   
                 Melanoma, OC, Uterine Cancer, 
               
               
                   
                   
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 208 
                 FLAVSLPLL 
                 CLL 
               
               
                   
               
               
                 209 
                 FLLDTISGL 
                 CRC, HCC, CLL, AML, BRCA, 
               
               
                   
                   
                 Melanoma, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 210 
                 FLAEQFEFL 
                 CLL 
               
               
                   
               
               
                 211 
                 FIDDLFAFV 
                 HCC, CLL, AML, Melanoma 
               
               
                   
               
               
                 212 
                 FLIGQGAHV 
                 CLL, AML, Melanoma 
               
               
                   
               
               
                 213 
                 YINEDEYEV 
                 CLL, OC 
               
               
                   
               
               
                 214 
                 FLFDGSMSL 
                 AML 
               
               
                   
               
               
                 215 
                 QLFEEEIEL 
                 RCC, Esophageal Cancer, OC, Uterine 
               
               
                   
                   
                 Cancer, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 216 
                 KVVSNLPAI 
                 AML, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 217 
                 AQFGAVLEV 
                 AML, Melanoma 
               
               
                   
               
               
                 218 
                 ALDQFLEGI 
                 CLL, BRCA, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 219 
                 ALLELENSV 
                 HCC, Uterine Cancer, Gallbladder 
               
               
                   
                   
                 Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 221 
                 FLAPDNSLLLA 
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 222 
                 FLIETGTLL 
                 CLL, BRCA, Uterine Cancer 
               
               
                   
               
               
                 223 
                 FLQDIPDGLFL 
                 CLL 
               
               
                   
               
               
                 224 
                 FLSPLLPLL 
                 HCC, CLL 
               
               
                   
               
               
                 225 
                 GTYQDVGSLNIGDV 
                 CLL 
               
               
                   
               
               
                 226 
                 GVIDPVPEV 
                 HCC, CLL, AML, Melanoma, OC, 
               
               
                   
                   
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 227 
                 IIAEGIPEA 
                 SCLC, CLL, Melanoma, Uterine Cancer 
               
               
                   
               
               
                 228 
                 IIAEYLSYV 
                 CLL 
               
               
                   
               
               
                 229 
                 ILSPWGAEV 
                 CLL, AML, Melanoma, Urinary bladder 
               
               
                   
                   
                 cancer 
               
               
                   
               
               
                 230 
                 IMDDDSYGV 
                 CLL 
               
               
                   
               
               
                 232 
                 KVMEGTVAA 
                 CLL 
               
               
                   
               
               
                 233 
                 MLEVHIPSV 
                 CLL 
               
               
                   
               
               
                 234 
                 NLQRTVVTV 
                 RCC, CLL, Uterine Cancer 
               
               
                   
               
               
                 235 
                 SLDVYELFL 
                 CRC, BRCA, Melanoma, Esophageal 
               
               
                   
                   
                 Cancer, OC, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer, Gallbladder Cancer, Bile 
               
               
                   
                   
                 Duct Cancer 
               
               
                   
               
               
                 236 
                 SLFDGFFLTA 
                 CLL, AML, Melanoma, Uterine Cancer 
               
               
                   
               
               
                 237 
                 YLDRLIPQA 
                 HCC, AML, Melanoma 
               
               
                   
               
               
                 238 
                 YQYGAVVTL 
                 CLL 
               
               
                   
               
               
                 239 
                 VLIDDTVLL 
                 HCC, AML, Melanoma 
               
               
                   
               
               
                 240 
                 ALVPTPALFYL 
                 BRCA 
               
               
                   
               
               
                 241 
                 FIPDFIPAV 
                 SCLC 
               
               
                   
               
               
                 242 
                 GILDFZVFL 
                 AML 
               
               
                   
               
               
                 243 
                 GLPDLDIYL 
                 HCC, CLL, AML, Melanoma, Uterine 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 244 
                 ILEPFLPAV 
                 Melanoma, Uterine Cancer 
               
               
                   
               
               
                 245 
                 KLIQLPVVYV 
                 CLL, BRCA, OC, Urinary bladder cancer 
               
               
                   
               
               
                 246 
                 KLPVPLESV 
                 CLL, Melanoma 
               
               
                   
               
               
                 247 
                 KVLEMETTV 
                 Uterine Cancer 
               
               
                   
               
               
                 248 
                 NLLEQFILL 
                 NSCLC, SCLC, RCC, Brain Cancer, 
               
               
                   
                   
                 CRC, HCC, CLL, AML, Melanoma, 
               
               
                   
                   
                 Urinary bladder cancer, Uterine Cancer 
               
               
                   
               
               
                 249 
                 VLLESLVEI 
                 Melanoma, Gallbladder Cancer, Bile Duct 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 250 
                 VLTNVGAAL 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 251 
                 VLYELFTYI 
                 CLL 
               
               
                   
               
               
                 252 
                 YLGDLIMAL 
                 CLL 
               
               
                   
               
               
                 253 
                 YSDDDVPSV 
                 NSCLC, SCLC, CLL, Melanoma, 
               
               
                   
                   
                 Esophageal Cancer, OC, Urinary bladder 
               
               
                   
                   
                 cancer, Uterine Cancer, Gallbladder 
               
               
                   
                   
                 Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 254 
                 FLYSETWNI 
                 HCC, CLL, AML, Melanoma 
               
               
                   
               
               
                 255 
                 GMWNPNAPVFL 
                 HCC, CLL, Uterine Cancer 
               
               
                   
               
               
                 257 
                 FLQEWEVYA 
                 CLL, AML, Melanoma, Urinary bladder 
               
               
                   
                   
                 cancer 
               
               
                   
               
               
                 258 
                 RIYPFLLMV 
                 NSCLC, SCLC, RCC, HCC, CLL, AML, 
               
               
                   
                   
                 Melanoma, Urinary bladder cancer, 
               
               
                   
                   
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 259 
                 TVLDGLEFKV 
                 SCLC, CLL, AML, Melanoma, Uterine 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 260 
                 RLDEAFDFV 
                 Melanoma, Urinary bladder cancer, 
               
               
                   
                   
                 Uterine Cancer 
               
               
                   
               
               
                 261 
                 FLPETRIMTSV 
                 SCLC, CLL, Melanoma, OC, Urinary 
               
               
                   
                   
                 bladder cancer 
               
               
                   
               
               
                 263 
                 GLMDNEIKV 
                 NSCLC, RCC, HCC, PC, Melanoma, 
               
               
                   
                   
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 264 
                 ILTGTPPGV 
                 BRCA 
               
               
                   
               
               
                 265 
                 ILWHFVASL 
                 CLL, Uterine Cancer 
               
               
                   
               
               
                 266 
                 QLTEMLPSI 
                 SCLC, HCC, Melanoma, Gallbladder 
               
               
                   
                   
                 Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 267 
                 SLLETGSDLLL 
                 HCC, Esophageal Cancer 
               
               
                   
               
               
                 268 
                 VLFPLPTPL 
                 CLL 
               
               
                   
               
               
                 270 
                 VVVDSDSLAFV 
                 SCLC, CLL, Melanoma, Uterine Cancer, 
               
               
                   
                   
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 271 
                 YLLDQPVLEQRL 
                 CLL, Melanoma 
               
               
                   
               
               
                 273 
                 AILLPQPPK 
                 RCC, CLL, Melanoma, OC 
               
               
                   
               
               
                 274 
                 KLLNLISKL 
                 AML 
               
               
                   
               
               
                 277 
                 FLIDLNSTHGTFL 
                 CLL 
               
               
                   
               
               
                 278 
                 FLLFINHRL 
                 CLL 
               
               
                   
               
               
                 279 
                 NLAGENILNPL 
                 CLL, Urinary bladder cancer, Uterine 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 280 
                 SLLNHLPYL 
                 CLL 
               
               
                   
               
               
                 281 
                 TLQTVPLTTV 
                 CLL 
               
               
                   
               
               
                 282 
                 YLLEQGAQV 
                 SCLC, HCC, CLL, Melanoma 
               
               
                   
               
               
                 283 
                 ALMPVTPQA 
                 CLL 
               
               
                   
               
               
                 284 
                 KLQEQIHRV 
                 AML 
               
               
                   
               
               
                 285 
                 SITAVTPLL 
                 RCC, AML 
               
               
                   
               
               
                 287 
                 ILMGHSLYM 
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 288 
                 RLAPEIVSA 
                 HCC 
               
               
                   
               
               
                 289 
                 SLLAANNLL 
                 HCC, Uterine Cancer, Gallbladder 
               
               
                   
                   
                 Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 290 
                 IASPVIAAV 
                 HCC, PC, CLL, AML, BRCA, Melanoma, 
               
               
                   
                   
                 Gallbladder Cancer, Bile Duct Cancer 
               
               
                   
               
               
                 291 
                 KIIDTAGLSEA 
                 CLL 
               
               
                   
               
               
                 292 
                 KLINSQISL 
                 CLL 
               
               
                   
               
               
                 293 
                 GLAMVEAISYV 
                 CLL, Urinary bladder cancer, Uterine 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 294 
                 KLYGPEGLELV 
                 CLL 
               
               
                   
               
               
                 296 
                 FILEPLYKI 
                 CLL, Esophageal Cancer, OC, Uterine 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 299 
                 RLLEEEGVSL 
                 CRC, AML, BRCA 
               
               
                   
               
               
                 301 
                 LQFDGIHVV 
                 SCLC, Brain Cancer 
               
               
                   
               
               
                 302 
                 SLAELDEKISA 
                 NSCLC, CLL, Melanoma, Esophageal 
               
               
                   
                   
                 Cancer, Urinary bladder cancer 
               
               
                   
                   
                 NSCLC, CLL, Esophageal Cancer, 
               
               
                   
               
               
                 303 
                 FVWEASHYL 
                 Uterine Cancer, Gallbladder Cancer, Bile 
               
               
                   
                   
                 Duct Cancer 
               
               
                   
               
               
                 304 
                 ALIRLDDLFL 
                 RCC, CLL, Melanoma 
               
               
                   
               
               
                 305 
                 AMLAQQMQL 
                 CLL, BRCA 
               
               
                   
               
               
                 306 
                 AQVALVNEV 
                 Urinary bladder cancer, Uterine Cancer 
               
               
                   
               
               
                 308 
                 SLLDQIPEM 
                 RCC, CLL, AML, BRCA, Melanoma, OC, 
               
               
                   
                   
                 Uterine Cancer, Gallbladder Cancer, Bile 
               
               
                   
                   
                 Duct Cancer 
               
               
                   
               
               
                 309 
                 SLSFVSPSL 
                 CLL, BRCA, Esophageal Cancer, Uterine 
               
               
                   
                   
                 Cancer 
               
               
                   
               
               
                 310 
                 VMAEAPPGV 
                 Uterine Cancer 
               
               
                   
               
               
                 311 
                 YLHRQVAAV 
                 SCLC, Melanoma, OC, Urinary bladder 
               
               
                   
                   
                 cancer 
               
               
                   
               
               
                 NSCLC = non-small cell lung cancer, SCLC = small cell lung cancer, RCC = kidney cancer, CRC = colon or rectum cancer, GC = stomach cancer, HCC = liver cancer, PC = pancreatic cancer, BRCA = breast cancer, OC = ovarian cancer, AML = acute myelogenous leukemia, CLL = chronic lymphocytic leukemia. 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 4B 
               
             
             
               
                   
               
               
                 Peptides according to the present invention and their specific uses in 
               
               
                 other proliferative diseases, especially in other cancerous diseases 
               
               
                 (amendment of Table 4A). The table shows, like Table 4A, for selected 
               
               
                 peptides on which additional tumor types they were found showing over- 
               
               
                 presentation (including specific presentation) on more than 5% of the 
               
               
                 measured tumor samples, or presentation on more than 5% of the measured 
               
               
                  tumor samples with a ratio of geometric means tumor vs normal tissues being 
               
               
                 larger than 3. Over-presentation is defined as higher presentation on the 
               
               
                 tumor sample as compared to the normal sample with highest presentation. 
               
               
                 Normal tissues against which over-presentation was tested were: adipose 
               
               
                 tissue, adrenal gland, artery, bone marrow, brain, central nerve, colon, 
               
               
                 duodenum, esophagus, eye, gallbladder, heart, kidney, liver, lung, 
               
               
                  lymph node, mononuclear white blood cells, pancreas, parathyroid gland, 
               
               
                 peripheral nerve, peritoneum, pituitary, pleura, rectum, salivary gland, 
               
               
                 skeletal muscle, skin, small intestine, spleen, stomach, thyroid gland, 
               
               
                 trachea, ureter, urinary bladder, vein. 
               
             
          
           
               
                 SEQ ID 
                   
                   
               
               
                 NO. 
                 Sequence 
                 Other relevant organs/diseases 
               
               
                   
               
             
          
           
               
                 2 
                 LLSEETPSA 
                 HNSCC 
               
               
                   
               
               
                 3 
                 LTIDTQYYL 
                 HNSCC 
               
               
                   
               
               
                 5 
                 VLQGLTFTL 
                 HNSCC 
               
               
                   
               
               
                 11 
                 GLDTVVALL 
                 HNSCC 
               
               
                   
               
               
                 12 
                 GLLLLVPLL 
                 OC, Esophageal Cancer, HNSCC 
               
               
                   
               
               
                 16 
                 TLIAAILYL 
                 SCLC, HNSCC 
               
               
                   
               
               
                 23 
                 ALVEDIINL 
                 Urinary Bladder Cancer, AML, HNSCC 
               
               
                   
               
               
                 24 
                 AVLGFSFRL 
                 AML 
               
               
                   
               
               
                 26 
                 FLGSFIDHV 
                 SCLC, AML 
               
               
                   
               
               
                 28 
                 FLSNANPSL 
                 SCLC, HNSCC 
               
               
                   
               
               
                 30 
                 ILSTLDVEL 
                 SCLC, Urinary Bladder Cancer, Gallbladder  
               
               
                   
                   
                 Cancer, Bile Duct Cancer, AML, HNSCC 
               
               
                   
               
               
                 33 
                 LLANIVPIAMLV 
                 Melanoma 
               
               
                   
               
               
                 36 
                 VILDIPLLFET 
                 SCLC, AML, HNSCC 
               
               
                   
               
               
                 37 
                 VLGNALEGV 
                 SCLC 
               
               
                   
               
               
                 38 
                 YLTAEILELAGN 
                 HNSCC 
               
               
                   
               
               
                 39 
                 QLLPQGIVPAL 
                 HCC 
               
               
                   
               
               
                 41 
                 ILASIFETV 
                 HNSCC 
               
               
                   
               
               
                 43 
                 ALLEGVKNV 
                 SCLC, BRCA 
               
               
                   
               
               
                 44 
                 FIIEEQSFL 
                 AML, HNSCC 
               
               
                   
               
               
                 46 
                 FLVEEIFQT 
                 AML 
               
               
                   
               
               
                 47 
                 GLLPKLTAL 
                 HNSCC 
               
               
                   
               
               
                 48 
                 KILDEDLYI 
                 AML, HNSCC 
               
               
                   
               
               
                 54 
                 DIFDAMFSV 
                 CLL 
               
               
                   
               
               
                 55 
                 ILVEVDLVQA 
                 Esophageal Cancer 
               
               
                   
               
               
                 56 
                 GLQDLLFSL 
                 Melanoma 
               
               
                   
               
               
                 60 
                 SLLIDVITV 
                 NSCLC, SCLC, GC, CRC, PC, BRCA, AML 
               
               
                   
               
               
                 61 
                 SLLNKDLSL 
                 Esophageal Cancer, AML, HNSCC 
               
               
                   
               
               
                 66 
                 KLAPIPVEL 
                 CLL, AML 
               
               
                   
               
               
                 67 
                 LLATVNVAL 
                 HNSCC 
               
               
                   
               
               
                 68 
                 QIAAFLFTV 
                 AML 
               
               
                   
               
               
                 69 
                 TLLAFPLLL 
                 HNSCC 
               
               
                   
               
               
                 70 
                 VLIEILQKA 
                 SCLC, HNSCC 
               
               
                   
               
               
                 71 
                 VLLDYVGNVQL 
                 HNSCC 
               
               
                   
               
               
                 73 
                 YLGEEYPEV 
                 HNSCC 
               
               
                   
               
               
                 76 
                 ALADLVPVDVV 
                 HNSCC 
               
               
                   
                 V 
                   
               
               
                   
               
               
                 88 
                 GLFDNRSGLPE 
                 AML, HNSCC 
               
               
                   
                 A 
                   
               
               
                   
               
               
                 95 
                 LLFDLIPVVSV 
                 HNSCC 
               
               
                   
               
               
                 96 
                 LLLNENESLFL 
                 HNSCC 
               
               
                   
               
               
                 99 
                 QLYDGATALFL 
                 HNSCC 
               
               
                   
               
               
                 103 
                 SLQDHLEKV 
                 Uterine Cancer 
               
               
                   
               
               
                 106 
                 VLYELLQYI 
                 HNSCC 
               
               
                   
               
               
                 107 
                 VQAVSIPEV 
                 CLL, AML 
               
               
                   
               
               
                 108 
                 YLAPENGYLM 
                 Uterine Cancer, AML, HNSCC 
               
               
                   
               
               
                 109 
                 YLFQFSAAL 
                 HNSCC 
               
               
                   
               
               
                 110 
                 YQYPFVLGL 
                 HNSCC 
               
               
                   
               
               
                 111 
                 YLLDTLLSL 
                 AML, HNSCC 
               
               
                   
               
               
                 115 
                 LLIDIIHFL 
                 AML 
               
               
                   
               
               
                 121 
                 YLTGYNFTL 
                 AML 
               
               
                   
               
               
                 122 
                 AISEAQESV 
                 HNSCC 
               
               
                   
               
               
                 124 
                 FLGVVVPTV 
                 AML, HNSCC 
               
               
                   
               
               
                 128 
                 KLFDASPTFFA 
                 OC, HNSCC 
               
               
                   
               
               
                 131 
                 VLIEETDQL 
                 BRCA 
               
               
                   
               
               
                 144 
                 GLITQVDKL 
                 Esophageal Cancer 
               
               
                   
               
               
                 146 
                 GLLQQPPAL 
                 HNSCC 
               
               
                   
               
               
                 152 
                 KIMYTLVSV 
                 AML 
               
               
                   
               
               
                 163 
                 SIFDAVLKGV 
                 HCC, Urinary Bladder Cancer, HNSCC 
               
               
                   
               
               
                 166 
                 SLFSEVASL 
                 AML 
               
               
                   
               
               
                 168 
                 SLLSPLLSV 
                 HNSCC 
               
               
                   
               
               
                 171 
                 TLLDVISAL 
                 HNSCC 
               
               
                   
               
               
                 179 
                 FVDTNLYFL 
                 AML 
               
               
                   
               
               
                 182 
                 LLPPPPPVA 
                 HNSCC 
               
               
                   
               
               
                 183 
                 VLFETVLTI 
                 HNSCC 
               
               
                   
               
               
                 185 
                 FIAQLNNVEL 
                 AML 
               
               
                   
               
               
                 188 
                 GLEDEMYEV 
                 HNSCC 
               
               
                   
               
               
                 191 
                 GLSDISAQV 
                 AML 
               
               
                   
               
               
                 194 
                 SLAPFDREPFT 
                 Melanoma, Gallbladder Cancer, Bile Duct Cancer, 
               
               
                   
                 L 
                 HNSCC 
               
               
                   
               
               
                 198 
                 GLLSAVSSV 
                 HNSCC 
               
               
                   
               
               
                 201 
                 YLNISQVNV 
                 AML 
               
               
                   
               
               
                 205 
                 TLFYESPHL 
                 CLL 
               
               
                   
               
               
                 212 
                 FLIGQGAHV 
                 HCC 
               
               
                   
               
               
                 213 
                 YINEDEYEV 
                 HNSCC 
               
               
                   
               
               
                 214 
                 FLFDGSMSL 
                 Urinary Bladder Cancer 
               
               
                   
               
               
                 216 
                 KVVSNLPAI 
                 RCC 
               
               
                   
               
               
                 217 
                 AQFGAVLEV 
                 RCC 
               
               
                   
               
               
                 218 
                 ALDQFLEGI 
                 HNSCC 
               
               
                   
               
               
                 220 
                 FLAEAPTAL 
                 AML 
               
               
                   
               
               
                 221 
                 FLAPDNSLLLA 
                 AML 
               
               
                   
               
               
                 224 
                 FLSPLLPLL 
                 AML 
               
               
                   
               
               
                 226 
                 GVIDPVPEV 
                 HNSCC 
               
               
                   
               
               
                 227 
                 IIAEGIPEA 
                 RCC, HNSCC 
               
               
                   
               
               
                 228 
                 IIAEYLSYV 
                 AML, HNSCC 
               
               
                   
               
               
                 235 
                 SLDVYELFL 
                 HNSCC 
               
               
                   
               
               
                 236 
                 SLFDGFFLTA 
                 RCC, GC 
               
               
                   
               
               
                 239 
                 VLIDDTVLL 
                 Uterine Cancer 
               
               
                   
               
               
                 240 
                 ALVPTPALFYL 
                 HNSCC 
               
               
                   
               
               
                 244 
                 ILEPFLPAV 
                 CLL, AML 
               
               
                   
               
               
                 246 
                 KLPVPLESV 
                 AML 
               
               
                   
               
               
                 247 
                 KVLEMETTV 
                 BRCA 
               
               
                   
               
               
                 248 
                 NLLEQFILL 
                 HNSCC 
               
               
                   
               
               
                 251 
                 VLYELFTYI 
                 AML, HNSCC 
               
               
                   
               
               
                 252 
                 YLGDLIMAL 
                 AML 
               
               
                   
               
               
                 253 
                 YSDDDVPSV 
                 AML, HNSCC 
               
               
                   
               
               
                 254 
                 FLYSETWNI 
                 HNSCC 
               
               
                   
               
               
                 255 
                 GMWNPNAPVF 
                 HNSCC 
               
               
                   
                 L 
                   
               
               
                   
               
               
                 256 
                 ALQETPPQV 
                 AML 
               
               
                   
               
               
                 258 
                 RIYPFLLMV 
                 CRC 
               
               
                   
               
               
                 259 
                 TVLDGLEFKV 
                 HNSCC 
               
               
                   
               
               
                 260 
                 RLDEAFDFV 
                 RCC, CLL 
               
               
                   
               
               
                 263 
                 GLMDNEIKV 
                 HNSCC 
               
               
                   
               
               
                 265 
                 ILWHFVASL 
                 AML 
               
               
                   
               
               
                 267 
                 SLLETGSDLLL 
                 Urinary Bladder Cancer, AML 
               
               
                   
               
               
                 268 
                 VLFPLPTPL 
                 AML 
               
               
                   
               
               
                 280 
                 SLLNHLPYL 
                 HNSCC 
               
               
                   
               
               
                 281 
                 TLQTVPLTTV 
                 AML 
               
               
                   
               
               
                 282 
                 YLLEQGAQV 
                 AML, HNSCC 
               
               
                   
               
               
                 289 
                 SLLAANNLL 
                 AML 
               
               
                   
               
               
                 290 
                 IASPVIAAV 
                 NSCLC, SCLC, CRC, Uterine Cancer 
               
               
                   
               
               
                 291 
                 KIIDTAGLSEA 
                 HNSCC 
               
               
                   
               
               
                 292 
                 KLINSQISL 
                 AML 
               
               
                   
               
               
                 296 
                 FILEPLYKI 
                 AML 
               
               
                   
               
               
                 297 
                 ILQNGLETL 
                 Gallbladder Cancer, Bile Duct Cancer, AML 
               
               
                   
               
               
                 299 
                 RLLEEEGVSL 
                 Melanoma 
               
               
                   
               
               
                 300 
                 IVLERNPEL 
                 AML 
               
               
                   
               
               
                 301 
                 LQFDGIHVV 
                 HNSCC 
               
               
                   
               
               
                 302 
                 SLAELDEKISA 
                 Uterine Cancer, HNSCC 
               
               
                   
               
               
                 303 
                 FVWEASHYL 
                 AML, HNSCC 
               
               
                   
               
               
                 306 
                 AQVALVNEV 
                 Esophageal Cancer, AML 
               
               
                   
               
               
                 307 
                 FLLPVAVKL 
                 HNSCC 
               
               
                   
               
               
                 308 
                 SLLDQIPEM 
                 HNSCC 
               
               
                   
               
               
                 309 
                 SLSFVSPSL 
                 AML, HNSCC 
               
               
                   
               
               
                 314 
                 LIDDKGTIKL 
                 Urinary Bladder Cancer 
               
               
                   
               
               
                 NSCLC = non-small cell lung cancer, SCLC = small cell lung cancer, RCC = kidney cancer, CRC = colon or rectum cancer, GC = stomach cancer, HCC = liver cancer, PC = pancreatic cancer, BRCA = breast cancer, CLL = chronic lymphocytic leukemia, AML = acute myeloid leukemia, OC = ovarian cancer, HNSCC = head and neck squamous cell carcinoma, head and neck cancer. 
               
             
          
         
       
     
         [0061]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 16, 17, 19, 20, 24, 25, 27, 28, 29, 31, 32, 33, 34, 36, 37, 39, 40, 41, 42, 43, 44, 45, 48, 50, 53, 54, 55, 56, 57, 59, 60, 63, 64, 65, 66, 67, 68, 69, 73, 76, 77, 80, 81, 82, 84, 85, 92, 96, 98, 101, 102, 103, 104, 105, 107, 114, 116, 122, 124, 128, 129, 131, 132, 138, 169, 179, 180, 182, 183, 184, 186, 188, 189, 190, 191, 195, 200, 201, 205, 206, 207, 208, 209, 210, 211, 212, 213, 218, 222, 223, 224, 225, 226, 227, 228, 229, 230, 232, 233, 234, 236, 238, 243, 244, 245, 246, 248, 250, 251, 252, 253, 254, 255, 257, 258, 259, 260, 261, 265, 268, 270, 271, 273, 277, 278, 279, 280, 281, 282, 283, 290, 291, 292, 293, 294, 296, 302, 303, 304, 305, 308, and 309 for the—in one preferred embodiment combined—treatment of CLL. 
         [0062]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 1, 2, 3, 5, 10, 11, 15, 23, 26, 27, 28, 29, 30, 31, 34, 36, 37, 38, 39, 42, 45, 47, 53, 55, 60, 61, 64, 65, 67, 68, 70, 73, 76, 80, 86, 87, 88, 95, 96, 103, 108, 110, 114, 117, 118, 121, 122, 124, 125, 129, 130, 148, 161, 163, 164, 179, 181, 183, 188, 190, 193, 195, 207, 209, 215, 218, 219, 222, 227, 234, 235, 236, 239, 243, 244, 247, 248, 250, 253, 255, 259, 260, 265, 270, 279, 289, 290, 293, 296, 302, 303, 306, 308, 309, and 310 for the—in one preferred embodiment combined—treatment of uterine cancer. 
         [0063]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 20, 38, 41, 194, 248, 253, 258, 263, 302, and 303 for the—in one preferred embodiment combined—treatment of NSCLC. 
         [0064]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 7, 8, 11, 16, 17, 31, 37, 41, 47, 56, 62, 69, 70, 79, 80, 92, 95, 104, 105, 116, 117, 120, 130, 132, 138, 144, 146, 148, 149, 165, 171, 180, 183, 184, 190, 198, 207, 209, 211, 212, 214, 216, 217, 226, 229, 236, 237, 239, 242, 243, 248, 254, 257, 258, 259, 274, 284, 285, 290, 299, 23, 24, 26, 30, 36, 44, 46, 48, 60, 61, 66, 68, 88, 107, 108, 111, 115, 121, 124, 152, 166, 179, 185, 191, 201, 220, 221, 224, 228, 244, 246, 251, 252, 253, 256, 265, 267, 268, 281, 282, 289, 292, 296, 297, 300, 303, 306, 309 and 308 for the—in one preferred embodiment combined—treatment of AML. 
         [0065]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 5, 10, 11, 15, 17, 20, 23, 27, 28, 29, 36, 38, 39, 41, 43, 48, 60, 70, 76, 93, 95, 96, 108, 122, 131, 163, 165, 181, 193, 197, 207, 209, 218, 222, 235, 240, 245, 247, 264, 290, 299, 305, 308, and 309 for the—in one preferred embodiment combined—treatment of BRCA. 
         [0066]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 5, 6, 7, 12, 13, 15, 17, 20, 23, 26, 30, 31, 33, 34, 36, 38, 40, 41, 43, 47, 48, 53, 56, 60, 62, 69, 73, 76, 83, 85, 86, 96, 98, 108, 116, 119, 124, 125, 126, 127, 129, 131, 132, 141, 165, 166, 174, 179, 180, 181, 182, 185, 188, 190, 191, 194, 203, 204, 207, 209, 211, 212, 217, 226, 227, 229, 235, 236, 237, 239, 243, 244, 246, 248, 249, 253, 254, 257, 258, 259, 260, 261, 263, 266, 270, 271, 273, 282, 290, 299, 302, 304, 308, and 311 for the—in one preferred embodiment combined—treatment of melanoma. 
         [0067]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 5, 7, 27, 34, 35, 37, 38, 39, 40, 41, 58, 60, 62, 68, 70, 77, 88, 108, 125, 126, 138, 181, 183, 209, 218, 229, 235, 245, 248, 253, 257, 258, 260, 261, 279, 293, 302, 306, 23, 30, 163, 214, 267, 314 and 311 for the—in one preferred embodiment combined—treatment of urinary bladder cancer. 
         [0068]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 5, 12, 16, 30, 34, 38, 41, 44, 46, 48, 69, 78, 87, 106, 108, 128, 129, 165, 188, 194, 198, 207, 215, 216, 219, 221, 226, 235, 249, 253, 258, 263, 266, 270, 287, 289, 290, 297, 303, and 308 for the—in one preferred embodiment combined—treatment of gallbladder cancer and/or bile duct cancer. 
         [0069]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 5, 12, 26, 35, 39, 43, 47, 58, 70, 77, 96, 108, 124, 128, 180, 185, 191, 207, 213, 215, 226, 235, 245, 253, 261, 273, 296, 308, and 311 for the—in one preferred embodiment combined—treatment of OC. 
         [0070]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 11, 23, 30, 34, 38, 47, 60, 73, 97, 108, 163, 184, 209, 235, 248, 258, 290, and 299 for the—in one preferred embodiment combined—treatment of CRC. 
         [0071]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 12, 21, 27, 31, 34, 44, 47, 48, 55, 59, 61, 77, 133, 144, 165, 191, 215, 235, 253, 267, 296, 302, 303, 306, and 309 for the—in one preferred embodiment combined—treatment of esophageal cancer. 
         [0072]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 20, 41, 47, 74, 78, 86, 93, 94, 100, 109, 122, 163, 165, 179, 181, 197, 215, 234, 248, 258, 263, 273, 285, 304, 216, 217, 227, 236, 260, and 308 for the—in one preferred embodiment combined—treatment of RCC. 
         [0073]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 37, 38, 39, 47, 69, 77, 96, 103, 108, 116, 152, 163, 169, 180, 181, 190, 207, 209, 211, 212, 219, 224, 226, 237, 239, 243, 248, 254, 255, 258, 263, 266, 267, 282, 288, 289, and 290 for the—in one preferred embodiment combined—treatment of HCC. 
         [0074]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 60, 109, 263, and 290 for the—in one preferred embodiment combined—treatment of PC. 
         [0075]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 47, 248, and 301 for the—in one preferred embodiment combined—treatment of brain cancer. 
         [0076]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 3, 5, 11, 12, 16, 23, 28, 30, 36, 38, 41, 44, 47, 48, 61, 67, 69, 70, 71, 73, 76, 88, 95, 96, 99, 106, 108, 109, 110, 111, 122, 124, 128, 146, 163, 168, 171, 182, 183, 188, 194, 198, 213, 218, 226, 227, 228, 235, 240, 248, 251, 253, 254, 255, 259, 263, 280, 282, 291, 301, 302, 303, 307, 308, and 309 for the—in one preferred embodiment combined—treatment of HNSCC. 
         [0077]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 2, 5, 16, 26, 28, 30, 36, 37, 38, 41, 43, 46, 60, 70, 73, 76, 90, 108, 117, 164, 182, 186, 207, 227, 241, 248, 253, 258, 259, 261, 266, 270, 282, 301, 311, and 290 for the—in one preferred embodiment combined—treatment of SCLC. 
         [0078]    Thus, another aspect of the present invention relates to the use of at least one peptide according to the present invention according to any one of SEQ ID No. 60, 74 and 236 for the—in one preferred embodiment combined—treatment of GC. 
         [0079]    Thus, another aspect of the present invention relates to the use of the peptides according to the present invention for the—preferably combined—treatment of a proliferative disease selected from the group of NHL, non-small cell lung cancer, small cell lung cancer, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanoma, ovarian cancer, urinary bladder cancer, uterine cancer, gallbladder and bile duct cancer. 
         [0080]    The present invention furthermore relates to peptides according to the present invention that have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or—in an elongated form, such as a length-variant—MHC class-II. 
         [0081]    The present invention further relates to the peptides according to the present invention wherein said peptides (each) consist or consist essentially of an amino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 311. 
         [0082]    The present invention further relates to the peptides according to the present invention, wherein said peptide is modified and/or includes non-peptide bonds. 
         [0083]    The present invention further relates to the peptides according to the present invention, wherein said peptide is part of a fusion protein, in particular fused to the N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii), or fused to (or into the sequence of) an antibody, such as, for example, an antibody that is specific for dendritic cells. 
         [0084]    The present invention further relates to a nucleic acid, encoding the peptides according to the present invention. The present invention further relates to the nucleic acid according to the present invention that is DNA, cDNA, PNA, RNA or combinations thereof. 
         [0085]    The present invention further relates to an expression vector capable of expressing and/or expressing a nucleic acid according to the present invention. 
         [0086]    The present invention further relates to a peptide according to the present invention, a nucleic acid according to the present invention or an expression vector according to the present invention for use in the treatment of diseases and in medicine, in particular in the treatment of cancer. 
         [0087]    The present invention further relates to antibodies that are specific against the peptides according to the present invention or complexes of said peptides according to the present invention with MHC, and methods of making these. 
         [0088]    The present invention further relates to T-cell receptors (TCRs), in particular soluble TCR (sTCRs) and in particular cloned TCRs engineered into autologous or allogeneic T cells, and methods of making these, as well as NK cells or other cells expressing and/or bearing said TCR or cross-reacting with said TCRs. 
         [0089]    The antibodies and TCRs are additional embodiments of the immunotherapeutic use of the peptides according to the invention at hand. 
         [0090]    The present invention further relates to a host cell comprising a nucleic acid according to the present invention or an expression vector as described before. The present invention further relates to the host cell according to the present invention that is an antigen presenting cell, and preferably is a dendritic cell. 
         [0091]    The present invention further relates to a method for producing a peptide according to the present invention, said method comprising culturing the host cell according to the present invention, and isolating the peptide from said host cell or its culture medium. 
         [0092]    The present invention further relates to said method according to the present invention, wherein the antigen is loaded onto class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or artificial antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell. 
         [0093]    The present invention further relates to the method according to the present invention, wherein the antigen-presenting cell comprises an expression vector capable of expressing or expressing said peptide containing SEQ ID No. 1 to SEQ ID No.: 311, preferably containing SEQ ID No. 1 to SEQ ID No. 217, or a variant amino acid sequence. 
         [0094]    The present invention further relates to activated T cells, produced by the method according to the present invention, wherein said T cell selectively recognizes a cell which expresses a polypeptide comprising an amino acid sequence according to the present invention. 
         [0095]    The present invention further relates to a method of killing target cells in a patient which target cells aberrantly express a polypeptide comprising any amino acid sequence according to the present invention, the method comprising administering to the patient an effective number of T cells as produced according to the present invention. 
         [0096]    The present invention further relates to the use of any peptide as described, the nucleic acid according to the present invention, the expression vector according to the present invention, the cell according to the present invention, the activated T lymphocyte, the T cell receptor or the antibody or other peptide- and/or peptide-MHC-binding molecules according to the present invention as a medicament or in the manufacture of a medicament. Preferably, said medicament is active against cancer. 
         [0097]    Preferably, said medicament is a cellular therapy, a vaccine or a protein based on a soluble TCR or antibody. 
         [0098]    The present invention further relates to a use according to the present invention, wherein said cancer cells are NHL, non-small cell lung cancer, small cell lung cancer, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanoma, ovarian cancer, urinary bladder cancer, uterine cancer, gallbladder and bile duct cancer, and preferably NHL cells. 
         [0099]    The present invention further relates to biomarkers based on the peptides according to the present invention, herein called “targets” that can be used in the diagnosis of cancer, preferably NHL. The marker can be over-presentation of the peptide(s) themselves, or over-expression of the corresponding gene(s). The markers may also be used to predict the probability of success of a treatment, preferably an immunotherapy, and most preferred an immunotherapy targeting the same target that is identified by the biomarker. For example, an antibody or soluble TCR can be used to stain sections of the tumor to detect the presence of a peptide of interest in complex with MHC. 
         [0100]    Optionally the antibody carries a further effector function such as an immune stimulating domain or toxin. 
         [0101]    The present invention also relates to the use of these novel targets in the context of cancer treatment. 
         [0102]    Both therapeutic and diagnostic uses against additional cancerous diseases are disclosed in the following description of the underlying expression products (polypeptides) of the peptides according to the invention. 
         [0103]    ACHE encodes acetylcholinesterase which hydrolyzes the neurotransmitter, acetylcholine at neuromuscular junctions and brain cholinergic synapses, and thus terminates signal transmission (RefSeq, 2002). ACHE may be a marker and regulator of apoptosis. It is involved in cell adhesion, differentiation, and proliferation and it is a promising tumor suppressor (Greig et al., 2013; Xi et al., 2015). ACHE and BCHE are involved in tumorigenesis but their relationship is not clear yet (Shan, 2004a). ACHE is abnormally expressed in meningioma, glioma, acoustic neurinoma, lung cancer, colon cancer, fibrosarcoma and ovarian cancer (Russo et al., 2006; Shan, 2004a; Shan, 2004b). Treatment of the Lambert-Eaton myasthenic syndrome, which has an idiopathic and a tumor-associated form, includes the usage of acetylcholinesterase inhibitors (Mareska and Gutmann, 2004; Verschuuren et al., 2006). Peptides spliced from the ACHE parent molecule as well as the parent protein itself can act independently as signaling molecule (Bukowska, 2005; Halliday and Greenfield, 2012). 
         [0104]    ACN9 (also known as succinate dehydrogenase complex assembly factor 3 (SDHAF3)) encodes ACN9 homolog and is located on chromosome 7q21.3 (RefSeq, 2002). Wrong or absent SDH complex assembly can result in cancer and neurodegenerative syndromes (Van Vranken et al., 2015). Various SNPs in ACN9 are associated with breast cancer (Kibriya et al., 2009). 
         [0105]    CDC42 encodes cell division cycle 42 which is a small GTPase of the Rho-subfamily, which regulates signaling pathways that control diverse cellular functions including cell morphology, migration, endocytosis and cell cycle progression (RefSeq, 2002). CDC42 controls epithelial as well as migratory polarity in combination with other regulators (Gandalovicova et al., 2016). c-Cbl is inhibited in glioblastomas and basal-like breast cancer through alteration of Cool-1/betapix and CDC42 (Noble et al., 2015). Exchange factors of CDC42, so called Dock family proteins, are involved in cancer (Gadea and Blangy, 2014). CDC42 is a RhoGTPase located at epithelial tight junctions (Lane et al., 2014; Zihni and Terry, 2015). CDC42 is able to activate STAT3 which is over-expressed in a variety of cancers (Raptis et al., 2011). CDC42 de-regulation is involved in cancer. It was shown that CDC42 signaling is involved in cellular transformation, cell division, cell invasion, migration, invadopodia formation, enzyme activity, filopodia formation, actin cytoskeleton alteration, and cell polarity. CDC42 regulates the invasion in glioblastoma (Stengel and Zheng, 2011; Albergaria et al., 2011; Kwiatkowska and Symons, 2013; Qadir et al., 2015; Lin and Zheng, 2015). Activated CDC42-associate kinase 1 (ACK1/TNK2) is an oncogenic kinase. p21-activated kinase (PAK) 5 is a downstream effector kinase of CDC42 and it is over-expressed in several cancer entities. PAK1 is up-regulated in cancer and is associated with tumor progression. Myotonic dystrophy-related CDC42-binding kinases (MRCK) are associated with human cancer (Mahajan and Mahajan, 2010; Eswaran et al., 2012; Maruta, 2014; Unbekandt and Olson, 2014; Dammann et al., 2014; Wen et al., 2014; Mahajan and Mahajan, 2015). CDC42 controls polarized atypical protein kinase C activity (Prehoda, 2009). The CDC42-IQGAP1 axis may drive  H. pylori -induced gastric carcinoma by negatively regulating the tumor suppressors E-cadherin and beta1-integrin (White et al., 2009; Osman et al., 2013). CDC42 is regulated via mTORC2 signaling and maybe via Notch signaling (Dotto, 2008; Zhou and Huang, 2011). Tiam1, GEFs, and RhoA are activators of CDC42 whereas Slit2 and Robo1 are inhibitors. CDC42 is regulated by CXCL12 and DLC-1 (Boissier and Huynh-Do, 2014; Sinha and Yang, 2008; Kim et al., 2009; Ben-Baruch, 2009; Xu et al., 2010; O&#39;Connor and Chen, 2013). CDC42 is a downstream effector of CD44 and HMGB1 resulting in angiogenesis, unlimited replicative potential, tissue invasion, and metastasis (Bourguignon, 2008; Hu et al., 2014). CDC42 is over-expressed in several cancer entities and may be correlated with poor prognosis. CDC42 over-expression in breast cancer may contribute to ErbB1 accumulation (Hirsch and Wu, 2007; Arias-Romero and Chernoff, 2013). The Golgi pool of CDC42 is regulated by a complex of GM130 and RasGRF. GM130 is progressively lost in colorectal cancer (Baschieri and Farhan, 2015). 
         [0106]    DCAKD encodes dephospho-CoA kinase domain containing and is located on chromosome 17q21.31 (RefSeq, 2002). DCAKD is up-regulated in breast cancer (Riis et al., 2012). 
         [0107]    HAPLN3 encodes hyaluronan and proteoglycan link protein 3 which may function in hyaluronic acid binding and cell adhesion (RefSeq, 2002). A three-gene signature including HAPLN3 can be used as methylation marker in prostate cancer (Strand et al., 2014). A gene fusion product of MFGE8 and HAPLN3 has been reported in breast cancer (Varley et al., 2014). HAPLN3 is hyper-methylated in prostate cancer (Haldrup et al., 2013). HAPLN3 is up-regulated in breast cancer and may be used as biomarker (Kuo et al., 2010). 
         [0108]    JAK3 encodes Janus Kinase 3, a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors (RefSeq, 2002). JAK3 is de-regulated in different cancer types including cutaneous T-cell lymphoma, extranodal nasal-type natural killer cell lymphoma, acute lymphoblastic leukemia, renal cell carcinoma and colon carcinoma (Lin et al., 2005; de et al., 2013; Bouchekioua et al., 2014; Sibbesen et al., 2015; Losdyck et al., 2015). JAK3 expression affects its down-stream targets STAT3, STATS, MAPK, pS6, the tumor suppressor microRNA miR-22, Bcl-2, Bcl-X, cyclin D2, p21 and p27. Therefore, JAK2 controls cell growth, apoptosis and cell cycle progression (Lin et al., 2005; Sibbesen et al., 2015; Agarwal et al., 2015). 
         [0109]    KDM2B encodes lysine demethylase 2B, a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination (RefSeq, 2002). KDM2B over-expression leads to enhanced cell migration by binding to migration-associated genes (Rohde et al., 2016). MiR-448, which is over-expressed in gastric cancer, down-regulates KDM2B. Myc is a key target of KDM2B (Hong et al., 2016). KDM2B mediates hematopoietic cell development and shows opposing roles in tumor progression (Andricovich et al., 2016). KDM2B is a co-repressor of BCL6 (Oliviero et al., 2015). KDM2B is involved in PI3K/mTOR pathway and promotes cell proliferation and inhibits cell apoptosis in nasopharyngeal carcinoma (Ren et al., 2015). Local generation of fumarate inhibits KDM2B resulting in the activation of DNA repair (Jiang et al., 2015). Depletion of KDM2B results in a p53-dependent growth arrest (Penzo et al., 2015). BCOR PFUD internal tandem duplications can be found in pediatric kidney and brain tumors. BCORL1 is part of the Polycomb Group Complex 1 (PRC1.1) which is recruited by KDM2B to facilitate gene repression. The PRC1.1 is important for leukemic stem cells and down-regulation of complex members like KDM2B reduces cell proliferation (Yamamoto et al., 2014; He et al., 2013; Blackledge et al., 2014; van den Boom et al., 2016; Wong et al., 2016). KDM2B is a non-Yamanaka factor involved in cell reprogramming (Liang et al., 2012; Liu et al., 2015). 
         [0110]    In bladder cancer, KDM2B is involved in cell proliferation, migration, and angiogenesis (Kottakis et al., 2011). KDM2B is over-expressed in several entities including basal-like triple-negative breast cancer and pancreatic cancer and regulates cell proliferation, chromatin structure, and senescence in HeLa cells. It is a positive regulator of glycolysis, glutaminolysis, and pyrimidine synthesis (Tzatsos et al., 2011; Tzatsos et al., 2013; Kottakis et al., 2014; Bacalini et al., 2015; Yu et al., 2015). KDM2B is an oncogene involved in leukemia development by impairing Nsg2-mediated differentiation (He et al., 2011; Nakamura et al., 2013; Ueda et al., 2015). KDM2B is a NF-kappaB-dependent anti-apoptotic protein. KDM2B-dependent degradation of c-Fos negatively regulates cell proliferation (Ge et al., 2011; Han et al., 2016). 
         [0111]    KDMSB encodes the protein JARID1B, a lysine-specific histone demethylase that is capable of repressing certain tumor suppressor genes by de-methylating lysine 4 of histone H3 (RefSeq, 2002). As epigenetic factor, KDMSB supports proliferation, migration and invasion of human OSCC, head and neck squamous cell carcinoma (HNSCC), breast cancer and lung cancer by suppressing p53 expression (Shen et al., 2015; Tang et al., 2015; Zhao and Liu, 2015; Lin et al., 2015). Also known as JARID1B, KDMSB promotes metastasis an epithelial-mesenchymal transition in various tumor types via PTEN/AKT signaling (Tang et al., 2015). 
         [0112]    PTTG1 encodes pituitary tumor-transforming 1. The encoded protein is a homolog of yeast securing proteins, which prevent separins from promoting sister chromatid separation. It is an anaphase-promoting complex (APC) substrate that associates with a separin until activation of the APC (RefSeq, 2002). PTTG1 is over-expressed in different cancer types including oral cancer, cervical cancer, breast cancer, prostate cancer and skin cancer. High protein levels are associated with metastasis and poor clinical outcome (Noll et al., 2015; Yoon et al., 2012; Huang et al., 2012; Zhang et al., 2014; Chen et al., 2015). PTTG1 is up-regulated in an mTOR complex 1-dependent manner. PTTG1 inhibits TGFbeta1-dependent phosphorylation of SMAD3 to promote cell growth (Zhang et al., 2015; Chen et al., 2016). PTTG2 encodes pituitary tumor-transforming 2 and it is located on chromosome 4p12 (RefSeq, 2002). Over-expression of the PTTG2 gene has been observed in high-grade glioma, whereas in liver cancer tissues from patients PTTG2 was not highly expressed (Yang et al., 2013; Cho-Rok et al., 2006). Elevated levels of PTTG2 were shown to promote cell proliferation and invasion during glioblastoma progression (Guo et al., 2016). 
         [0113]    SMC2 (also called CAP-E or SMC2L1) encodes a member of the structural maintenance of chromosomes family which is critical for mitotic chromosome condensation and DNA repair (RefSeq, 2002). The SMC2 gene is altered by frameshift mutation and loss of expression in gastric and colorectal cancer with microsatellite instability suggesting that SMC2 might be involved in tumor pathogenesis (Je et al., 2014). SMC2 gene alterations can play a role in genome instability, which accelerates the accumulation of other alterations in pyothorax-associated lymphomas (Ham et al., 2007). 
         [0114]    TMEM67 encodes transmembrane protein 67 and is localized to the primary cilium and to the plasma membrane. The gene functions in centriole migration to the apical membrane and formation of the primary cilium. Defects in this gene are a cause of Meckel syndrome type 3 (MKS3) and Joubert syndrome type 6 (JBTS6) (RefSeq, 2002). TMEM67 is involved in cilia formation and defective cilia may cause ocular coloboma, tongue tumors, and medulloblastoma (Han et al., 2010; Parisi, 2009; Yang et al., 2015; Han and Alvarez-Buylla, 2010). 
         [0115]    Stimulation of an immune response is dependent upon the presence of antigens recognized as foreign by the host immune system. The discovery of the existence of tumor associated antigens has raised the possibility of using a host&#39;s immune system to intervene in tumor growth. Various mechanisms of harnessing both the humoral and cellular arms of the immune system are currently being explored for cancer immunotherapy. 
         [0116]    Specific elements of the cellular immune response are capable of specifically recognizing and destroying tumor cells. The isolation of T-cells from tumor-infiltrating cell populations or from peripheral blood suggests that such cells play an important role in natural immune defense against cancer. CD8-positive T-cells in particular, which recognize class I molecules of the major histocompatibility complex (MHC)-bearing peptides of usually 8 to 10 amino acid residues derived from proteins or defect ribosomal products (DRIPS) located in the cytosol, play an important role in this response. The MHC-molecules of the human are also designated as human leukocyte-antigens (HLA). 
         [0117]    The term “T-cell response” means the specific proliferation and activation of effector functions induced by a peptide in vitro or in vivo. For MHC class I restricted cytotoxic T cells, effector functions may be lysis of peptide-pulsed, peptide-precursor pulsed or naturally peptide-presenting target cells, secretion of cytokines, preferably Interferon-gamma, TNF-alpha, or IL-2 induced by peptide, secretion of effector molecules, preferably granzymes or perforins induced by peptide, or degranulation. 
         [0118]    The term “peptide” is used herein to designate a series of amino acid residues, connected one to the other typically by peptide bonds between the alpha-amino and carbonyl groups of the adjacent amino acids. The peptides are preferably 9 amino acids in length, but can be as short as 8 amino acids in length, and as long as 10, 11, 12, 13, or 14 or longer, and in case of MHC class II peptides (elongated variants of the peptides of the invention) they can be as long as 14, 15, 16, 17, 18, 19 or 20 or more amino acids in length. 
         [0119]    Furthermore, the term “peptide” shall include salts of a series of amino acid residues, connected one to the other typically by peptide bonds between the alpha-amino and carbonyl groups of the adjacent amino acids. Preferably, the salts are pharmaceutical acceptable salts of the peptides, such as, for example, the chloride or acetate (trifluoroacetate) salts. It has to be noted that the salts of the peptides according to the present invention differ substantially from the peptides in their state(s) in vivo, as the peptides are not salts in vivo. 
         [0120]    The term “peptide” shall also include “oligopeptide”. The term “oligopeptide” is used herein to designate a series of amino acid residues, connected one to the other typically by peptide bonds between the alpha-amino and carbonyl groups of the adjacent amino acids. 
         [0121]    The length of the oligopeptide is not critical to the invention, as long as the correct epitope or epitopes are maintained therein. The oligopeptides are typically less than about 30 amino acid residues in length, and greater than about 15 amino acids in length. 
         [0122]    The term “polypeptide” designates a series of amino acid residues, connected one to the other typically by peptide bonds between the alpha-amino and carbonyl groups of the adjacent amino acids. The length of the polypeptide is not critical to the invention as long as the correct epitopes are maintained. In contrast to the terms peptide or oligopeptide, the term polypeptide is meant to refer to molecules containing more than about 30 amino acid residues. 
         [0123]    A peptide, oligopeptide, protein or polynucleotide coding for such a molecule is “immunogenic” (and thus is an “immunogen” within the present invention), if it is capable of inducing an immune response. In the case of the present invention, immunogenicity is more specifically defined as the ability to induce a T-cell response. Thus, an “immunogen” would be a molecule that is capable of inducing an immune response, and in the case of the present invention, a molecule capable of inducing a T-cell response. In another aspect, the immunogen can be the peptide, the complex of the peptide with MHC, oligopeptide, and/or protein that is used to raise specific antibodies or TCRs against it. 
         [0124]    A class I T cell “epitope” requires a short peptide that is bound to a class I MHC receptor, forming a ternary complex (MHC class I alpha chain, beta-2-microglobulin, and peptide) that can be recognized by a T cell bearing a matching T-cell receptor binding to the MHC/peptide complex with appropriate affinity. Peptides binding to MHC class I molecules are typically 8-14 amino acids in length, and most typically 9 amino acids in length. 
         [0125]    In humans, there are three different genetic loci that encode MHC class I molecules (the MHC-molecules of the human are also designated human leukocyte antigens (HLA)): HLA-A, HLA-B, and HLA-C. HLA-A*01, HLA-A*02, and HLA-B*07 are examples of different MHC class I alleles that can be expressed from these loci. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Expression frequencies F of HLA-A*02 and HLA-A*24 and the most 
               
               
                 frequent HLA-DR serotypes. Frequencies are deduced from haplotype 
               
               
                 frequencies Gf within the American population adapted from Mori et al. 
               
               
                 (Mori et al., 1997) employing the Hardy-Weinberg formula F = 1 − 
               
               
                 (1 − Gf) 2 . Combinations of A*02 or A*24 with certain HLA-DR 
               
               
                 alleles might be enriched or less frequent than expected from their 
               
               
                 single frequencies due to linkage disequilibrium. For details refer 
               
               
                 to Chanock et al. (Chanock et al., 2004). 
               
             
          
           
               
                   
                   
                 Calculated phenotype 
               
               
                 Allele 
                 Population 
                 from allele frequency 
               
               
                   
               
               
                 A*02 
                 Caucasian (North America) 
                  49.1% 
               
               
                 A*02 
                 African American (North America) 
                  34.1% 
               
               
                 A*02 
                 Asian American (North America) 
                  43.2% 
               
               
                 A*02 
                 Latin American (North American) 
                  48.3% 
               
               
                 DR1 
                 Caucasian (North America) 
                  19.4% 
               
               
                 DR2 
                 Caucasian (North America) 
                  28.2% 
               
               
                 DR3 
                 Caucasian (North America) 
                  20.6% 
               
               
                 DR4 
                 Caucasian (North America) 
                  30.7% 
               
               
                 DR5 
                 Caucasian (North America) 
                  23.3% 
               
               
                 DR6 
                 Caucasian (North America) 
                  26.7% 
               
               
                 DR7 
                 Caucasian (North America) 
                  24.8% 
               
               
                 DR8 
                 Caucasian (North America) 
                  5.7% 
               
               
                 DR9 
                 Caucasian (North America) 
                  2.1% 
               
               
                 DR1 
                 African (North) American 
                 13.20% 
               
               
                 DR2 
                 African (North) American 
                 29.80% 
               
               
                 DR3 
                 African (North) American 
                 24.80% 
               
               
                 DR4 
                 African (North) American 
                 11.10% 
               
               
                 DR5 
                 African (North) American 
                 31.10% 
               
               
                 DR6 
                 African (North) American 
                 33.70% 
               
               
                 DR7 
                 African (North) American 
                 19.20% 
               
               
                 DR8 
                 African (North) American 
                 12.10% 
               
               
                 DR9 
                 African (North) American 
                  5.80% 
               
               
                 DR1 
                 Asian (North) American 
                  6.80% 
               
               
                 DR2 
                 Asian (North) American 
                 33.80% 
               
               
                 DR3 
                 Asian (North) American 
                  9.20% 
               
               
                 DR4 
                 Asian (North) American 
                 28.60% 
               
               
                 DR5 
                 Asian (North) American 
                 30.00% 
               
               
                 DR6 
                 Asian (North) American 
                 25.10% 
               
               
                 DR7 
                 Asian (North) American 
                 13.40% 
               
               
                 DR8 
                 Asian (North) American 
                 12.70% 
               
               
                 DR9 
                 Asian (North) American 
                 18.60% 
               
               
                 DR1 
                 Latin (North) American 
                 15.30% 
               
               
                 DR2 
                 Latin (North) American 
                 21.20% 
               
               
                 DR3 
                 Latin (North) American 
                 15.20% 
               
               
                 DR4 
                 Latin (North) American 
                 36.80% 
               
               
                 DR5 
                 Latin (North) American 
                 20.00% 
               
               
                 DR6 
                 Latin (North) American 
                 31.10% 
               
               
                 DR7 
                 Latin (North) American 
                 20.20% 
               
               
                 DR8 
                 Latin (North) American 
                 18.60% 
               
               
                 DR9 
                 Latin (North) American 
                  2.10% 
               
               
                 A*24 
                 Philippines 
                   65% 
               
               
                 A*24 
                 Russia Nenets 
                   61% 
               
               
                 A*24:02 
                 Japan 
                   59% 
               
               
                 A*24 
                 Malaysia 
                   58% 
               
               
                 A*24:02 
                 Philippines 
                   54% 
               
               
                 A*24 
                 India 
                   47% 
               
               
                 A*24 
                 South Korea 
                   40% 
               
               
                 A*24 
                 Sri Lanka 
                   37% 
               
               
                 A*24 
                 China 
                   32% 
               
               
                 A*24:02 
                 India 
                   29% 
               
               
                 A*24 
                 Australia West 
                   22% 
               
               
                 A*24 
                 USA 
                   22% 
               
               
                 A*24 
                 Russia Samara 
                   20% 
               
               
                 A*24 
                 South America 
                   20% 
               
               
                 A*24 
                 Europe 
                   18% 
               
               
                   
               
             
          
         
       
     
         [0126]    The peptides of the invention, preferably when included into a vaccine of the invention as described herein bind to A*02. A vaccine may also include pan-binding MHC class II peptides. Therefore, the vaccine of the invention can be used to treat cancer in patients that are A*02 positive, whereas no selection for MHC class II allotypes is necessary due to the pan-binding nature of these peptides. 
         [0127]    If A*02 peptides of the invention are combined with peptides binding to another allele, for example A*24, a higher percentage of any patient population can be treated compared with addressing either MHC class I allele alone. While in most populations less than 50% of patients could be addressed by either allele alone, a vaccine comprising HLA-A*24 and HLA-A*02 epitopes can treat at least 60% of patients in any relevant population. Specifically, the following percentages of patients will be positive for at least one of these alleles in various regions: USA 61%, Western Europe 62%, China 75%, South Korea 77%, Japan 86% (calculated from www.allelefrequencies.net). 
         [0128]    In a preferred embodiment, the term “nucleotide sequence” refers to a heteropolymer of deoxyribonucleotides. 
         [0129]    The nucleotide sequence coding for a particular peptide, oligopeptide, or polypeptide may be naturally occurring or they may be synthetically constructed. Generally, DNA segments encoding the peptides, polypeptides, and proteins of this invention are assembled from cDNA fragments and short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic gene that is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon. 
         [0130]    As used herein the term “a nucleotide coding for (or encoding) a peptide” refers to a nucleotide sequence coding for the peptide including artificial (man-made) start and stop codons compatible for the biological system the sequence is to be expressed by, for example, a dendritic cell or another cell system useful for the production of TCRs. 
         [0131]    As used herein, reference to a nucleic acid sequence includes both single stranded and double stranded nucleic acid. Thus, for example for DNA, the specific sequence, unless the context indicates otherwise, refers to the single strand DNA of such sequence, the duplex of such sequence with its complement (double stranded DNA) and the complement of such sequence. 
         [0132]    The term “coding region” refers to that portion of a gene which either naturally or normally codes for the expression product of that gene in its natural genomic environment, i.e., the region coding in vivo for the native expression product of the gene. 
         [0133]    The coding region can be derived from a non-mutated (“normal”), mutated or altered gene, or can even be derived from a DNA sequence, or gene, wholly synthesized in the laboratory using methods well known to those of skill in the art of DNA synthesis. 
         [0134]    The term “expression product” means the polypeptide or protein that is the natural translation product of the gene and any nucleic acid sequence coding equivalents resulting from genetic code degeneracy and thus coding for the same amino acid(s). 
         [0135]    The term “fragment”, when referring to a coding sequence, means a portion of DNA comprising less than the complete coding region, whose expression product retains essentially the same biological function or activity as the expression product of the complete coding region. 
         [0136]    The term “DNA segment” refers to a DNA polymer, in the form of a separate fragment or as a component of a larger DNA construct, which has been derived from DNA isolated at least once in substantially pure form, i.e., free of contaminating endogenous materials and in a quantity or concentration enabling identification, manipulation, and recovery of the segment and its component nucleotide sequences by standard biochemical methods, for example, by using a cloning vector. Such segments are provided in the form of an open reading frame uninterrupted by internal non-translated sequences, or introns, which are typically present in eukaryotic genes. Sequences of non-translated DNA may be present downstream from the open reading frame, where the same do not interfere with manipulation or expression of the coding regions. 
         [0137]    The term “primer” means a short nucleic acid sequence that can be paired with one strand of DNA and provides a free 3′-OH end at which a DNA polymerase starts synthesis of a deoxyribonucleotide chain. 
         [0138]    The term “promoter” means a region of DNA involved in binding of RNA polymerase to initiate transcription. 
         [0139]    The term “isolated” means that the material is removed from its original environment (e.g., the natural environment, if it is naturally occurring). For example, a naturally-occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, separated from some or all of the coexisting materials in the natural system, is isolated. Such polynucleotides could be part of a vector and/or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of its natural environment. 
         [0140]    The polynucleotides, and recombinant or immunogenic polypeptides, disclosed in accordance with the present invention may also be in “purified” form. The term “purified” does not require absolute purity; rather, it is intended as a relative definition, and can include preparations that are highly purified or preparations that are only partially purified, as those terms are understood by those of skill in the relevant art. For example, individual clones isolated from a cDNA library have been conventionally purified to electrophoretic homogeneity. Purification of starting material or natural material to at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated. Furthermore, a claimed polypeptide which has a purity of preferably 99.999%, or at least 99.99% or 99.9%; and even desirably 99% by weight or greater is expressly encompassed. 
         [0141]    The nucleic acids and polypeptide expression products disclosed according to the present invention, as well as expression vectors containing such nucleic acids and/or such polypeptides, may be in “enriched form”. As used herein, the term “enriched” means that the concentration of the material is at least about 2, 5, 10, 100, or 1000 times its natural concentration (for example), advantageously 0.01%, by weight, preferably at least about 0.1% by weight. Enriched preparations of about 0.5%, 1%, 5%, 10%, and 20% by weight are also contemplated. The sequences, constructs, vectors, clones, and other materials comprising the present invention can advantageously be in enriched or isolated form. The term “active fragment” means a fragment, usually of a peptide, polypeptide or nucleic acid sequence, that generates an immune response (i.e., has immunogenic activity) when administered, alone or optionally with a suitable adjuvant or in a vector, to an animal, such as a mammal, for example, a rabbit or a mouse, and also including a human, such immune response taking the form of stimulating a T-cell response within the recipient animal, such as a human. Alternatively, the “active fragment” may also be used to induce a T-cell response in vitro. 
         [0142]    As used herein, the terms “portion”, “segment” and “fragment”, when used in relation to polypeptides, refer to a continuous sequence of residues, such as amino acid residues, which sequence forms a subset of a larger sequence. For example, if a polypeptide were subjected to treatment with any of the common endopeptidases, such as trypsin or chymotrypsin, the oligopeptides resulting from such treatment would represent portions, segments or fragments of the starting polypeptide. When used in relation to polynucleotides, these terms refer to the products produced by treatment of said polynucleotides with any of the endonucleases. 
         [0143]    In accordance with the present invention, the term “percent identity” or “percent identical”, when referring to a sequence, means that a sequence is compared to a claimed or described sequence after alignment of the sequence to be compared (the “Compared Sequence”) with the described or claimed sequence (the “Reference Sequence”). The percent identity is then determined according to the following formula: 
         [0000]      percent identity=100[1−( C/R )]
 
         [0000]    wherein C is the number of differences between the Reference Sequence and the Compared Sequence over the length of alignment between the Reference Sequence and the Compared Sequence, wherein
 
(i) each base or amino acid in the Reference Sequence that does not have a corresponding aligned base or amino acid in the Compared Sequence and
 
(ii) each gap in the Reference Sequence and
 
(iii) each aligned base or amino acid in the Reference Sequence that is different from an aligned base or amino acid in the Compared Sequence, constitutes a difference and
 
(iiii) the alignment has to start at position 1 of the aligned sequences;
 
and R is the number of bases or amino acids in the Reference Sequence over the length of the alignment with the Compared Sequence with any gap created in the Reference Sequence also being counted as a base or amino acid.
 
         [0144]    If an alignment exists between the Compared Sequence and the Reference Sequence for which the percent identity as calculated above is about equal to or greater than a specified minimum Percent Identity then the Compared Sequence has the specified minimum percent identity to the Reference Sequence even though alignments may exist in which the herein above calculated percent identity is less than the specified percent identity. 
         [0145]    As mentioned above, the present invention thus provides a peptide comprising a sequence that is selected from the group of consisting of SEQ ID NO: 1 to SEQ ID NO: 311 or a variant thereof which is 88% homologous to SEQ ID NO: 1 to SEQ ID NO: 311, or a variant thereof that will induce T cells cross-reacting with said peptide. The peptides of the invention have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or elongated versions of said peptides to class II. 
         [0146]    In the present invention, the term “homologous” refers to the degree of identity (see percent identity above) between sequences of two amino acid sequences, i.e. peptide or polypeptide sequences. The aforementioned “homology” is determined by comparing two sequences aligned under optimal conditions over the sequences to be compared. Such a sequence homology can be calculated by creating an alignment using, for example, the ClustalW algorithm. Commonly available sequence analysis software, more specifically, Vector NTI, GENETYX or other tools are provided by public databases. 
         [0147]    A person skilled in the art will be able to assess, whether T cells induced by a variant of a specific peptide will be able to cross-react with the peptide itself (Appay et al., 2006; Colombetti et al., 2006; Fong et al., 2001; Zaremba et al., 1997). 
         [0148]    By a “variant” of the given amino acid sequence the inventors mean that the side chains of, for example, one or two of the amino acid residues are altered (for example by replacing them with the side chain of another naturally occurring amino acid residue or some other side chain) such that the peptide is still able to bind to an HLA molecule in substantially the same way as a peptide consisting of the given amino acid sequence in consisting of SEQ ID NO: 1 to SEQ ID NO: 311. For example, a peptide may be modified so that it at least maintains, if not improves, the ability to interact with and bind to the binding groove of a suitable MHC molecule, such as HLA-A*02 or -DR, and in that way, it at least maintains, if not improves, the ability to bind to the TCR of activated T cells. 
         [0149]    These T cells can subsequently cross-react with cells and kill cells that express a polypeptide that contains the natural amino acid sequence of the cognate peptide as defined in the aspects of the invention. As can be derived from the scientific literature and databases (Rammensee et al., 1999; Godkin et al., 1997), certain positions of HLA binding peptides are typically anchor residues forming a core sequence fitting to the binding motif of the HLA receptor, which is defined by polar, electrophysical, hydrophobic and spatial properties of the polypeptide chains constituting the binding groove. Thus, one skilled in the art would be able to modify the amino acid sequences set forth in SEQ ID NO: 1 to SEQ ID NO 311, by maintaining the known anchor residues, and would be able to determine whether such variants maintain the ability to bind MHC class I or II molecules. The variants of the present invention retain the ability to bind to the TCR of activated T cells, which can subsequently cross-react with and kill cells that express a polypeptide containing the natural amino acid sequence of the cognate peptide as defined in the aspects of the invention. 
         [0150]    The original (unmodified) peptides as disclosed herein can be modified by the substitution of one or more residues at different, possibly selective, sites within the peptide chain, if not otherwise stated. Preferably those substitutions are located at the end of the amino acid chain. Such substitutions may be of a conservative nature, for example, where one amino acid is replaced by an amino acid of similar structure and characteristics, such as where a hydrophobic amino acid is replaced by another hydrophobic amino acid. Even more conservative would be replacement of amino acids of the same or similar size and chemical nature, such as where leucine is replaced by isoleucine. In studies of sequence variations in families of naturally occurring homologous proteins, certain amino acid substitutions are more often tolerated than others, and these are often show correlation with similarities in size, charge, polarity, and hydrophobicity between the original amino acid and its replacement, and such is the basis for defining “conservative substitutions.” 
         [0151]    Conservative substitutions are herein defined as exchanges within one of the following five groups: Group 1-small aliphatic, nonpolar or slightly polar residues (Ala, Ser, Thr, Pro, Gly); Group 2-polar, negatively charged residues and their amides (Asp, Asn, Glu, Gln); Group 3-polar, positively charged residues (His, Arg, Lys); Group 4-large, aliphatic, nonpolar residues (Met, Leu, Ile, Val, Cys); and Group 5-large, aromatic residues (Phe, Tyr, Trp). 
         [0152]    Less conservative substitutions might involve the replacement of one amino acid by another that has similar characteristics but is somewhat different in size, such as replacement of an alanine by an isoleucine residue. Highly non-conservative replacements might involve substituting an acidic amino acid for one that is polar, or even for one that is basic in character. Such “radical” substitutions cannot, however, be dismissed as potentially ineffective since chemical effects are not totally predictable and radical substitutions might well give rise to serendipitous effects not otherwise predictable from simple chemical principles. 
         [0153]    Of course, such substitutions may involve structures other than the common L-amino acids. Thus, D-amino acids might be substituted for the L-amino acids commonly found in the antigenic peptides of the invention and yet still be encompassed by the disclosure herein. In addition, non-standard amino acids (i.e., other than the common naturally occurring proteinogenic amino acids) may also be used for substitution purposes to produce immunogens and immunogenic polypeptides according to the present invention. 
         [0154]    If substitutions at more than one position are found to result in a peptide with substantially equivalent or greater antigenic activity as defined below, then combinations of those substitutions will be tested to determine if the combined substitutions result in additive or synergistic effects on the antigenicity of the peptide. At most, no more than 4 positions within the peptide would be simultaneously substituted. 
         [0155]    A peptide consisting essentially of the amino acid sequence as indicated herein can have one or two non-anchor amino acids (see below regarding the anchor motif) exchanged without that the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or -II is substantially changed or is negatively affected, when compared to the non-modified peptide. In another embodiment, in a peptide consisting essentially of the amino acid sequence as indicated herein, one or two amino acids can be exchanged with their conservative exchange partners (see herein below) without that the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or -II is substantially changed, or is negatively affected, when compared to the non-modified peptide. 
         [0156]    The amino acid residues that do not substantially contribute to interactions with the T-cell receptor can be modified by replacement with other amino acids whose incorporation do not substantially affect T-cell reactivity and does not eliminate binding to the relevant MHC. Thus, apart from the proviso given, the peptide of the invention may be any peptide (by which term the inventors include oligopeptide or polypeptide), which includes the amino acid sequences or a portion or variant thereof as given. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Variants and motif of the peptides according to SEQ ID NO: 2, 5, and 8. 
               
             
          
           
               
                   
                 Position 
               
             
          
           
               
                   
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
               
               
                   
               
               
                 SEQ ID NO. 2 
                 L 
                 L 
                 S 
                 E 
                 E 
                 T 
                 P 
                 S 
                 A 
               
               
                 Variants 
                   
                   
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
                   
                 M 
               
               
                   
                   
                 M 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 M 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 M 
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
                   
                 A 
               
               
                   
                   
                 A 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 A 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 A 
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
                   
                 V 
               
               
                   
                   
                 V 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 V 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 V 
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
                   
                 T 
               
               
                   
                   
                 T 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 T 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 T 
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
                   
                 Q 
               
               
                   
                   
                 Q 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 Q 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 Q 
                   
                   
                   
                   
                   
                   
                 L 
               
               
                 SEQ ID NO 5 
                 V 
                 L 
                 Q 
                 G 
                 L 
                 T 
                 F 
                 T 
                 L 
               
               
                 Variants 
                   
                   
                   
                   
                   
                   
                   
                   
                 A 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 M 
               
               
                   
                   
                 M 
                   
                   
                   
                   
                   
                   
                 A 
               
               
                   
                   
                 M 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 M 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 A 
               
               
                   
                   
                 A 
                   
                   
                   
                   
                   
                   
                 A 
               
               
                   
                   
                 A 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 A 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 V 
               
               
                   
                   
                 V 
                   
                   
                   
                   
                   
                   
                 A 
               
               
                   
                   
                 V 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 V 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 T 
               
               
                   
                   
                 T 
                   
                   
                   
                   
                   
                   
                 A 
               
               
                   
                   
                 T 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 T 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 Q 
               
               
                   
                   
                 Q 
                   
                   
                   
                   
                   
                   
                 A 
               
               
                   
                   
                 Q 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 Q 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                 SEQ ID NO. 8 
                 A 
                 L 
                 Y 
                 A 
                 V 
                 I 
                 E 
                 K 
                 A 
               
               
                 Variants 
                   
                   
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
                   
                 M 
               
               
                   
                   
                 M 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 M 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 M 
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
                   
                 A 
               
               
                   
                   
                 A 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 A 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 A 
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
                   
                 V 
               
               
                   
                   
                 V 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 V 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 V 
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
                   
                 T 
               
               
                   
                   
                 T 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 T 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 T 
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
                   
                 Q 
               
               
                   
                   
                 Q 
                   
                   
                   
                   
                   
                   
                 V 
               
               
                   
                   
                 Q 
                   
                   
                   
                   
                   
                   
                 I 
               
               
                   
                   
                 Q 
                   
                   
                   
                   
                   
                   
                 L 
               
               
                   
               
             
          
         
       
     
         [0157]    Longer (elongated) peptides may also be suitable. It is possible that MHC class I epitopes, although usually between 8 and 11 amino acids long, are generated by peptide processing from longer peptides or proteins that include the actual epitope. It is preferred that the residues that flank the actual epitope are residues that do not substantially affect proteolytic cleavage necessary to expose the actual epitope during processing. 
         [0158]    The peptides of the invention can be elongated by up to four amino acids, that is 1, 2, 3 or 4 amino acids can be added to either end in any combination between 4:0 and 0:4. Combinations of the elongations according to the invention can be found in Table 7. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                 Combinations of the elongations of peptides of the invention 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 C-terminus 
                 N-terminus 
               
               
                   
                   
               
               
                   
                 4 
                 0 
               
               
                   
                 3 
                 0 or 1 
               
               
                   
                 2 
                 0 or 1 or 2 
               
               
                   
                 1 
                 0 or 1 or 2 or 3 
               
               
                   
                 0 
                 0 or 1 or 2 or 3 or 4 
               
               
                   
                   
               
               
                   
                 N-terminus 
                 C-terminus 
               
               
                   
                   
               
               
                   
                 4 
                 0 
               
               
                   
                 3 
                 0 or 1 
               
               
                   
                 2 
                 0 or 1 or 2 
               
               
                   
                 1 
                 0 or 1 or 2 or 3 
               
               
                   
                 0 
                 0 or 1 or 2 or 3 or 4 
               
               
                   
                   
               
             
          
         
       
     
         [0159]    The amino acids for the elongation/extension can be the peptides of the original sequence of the protein or any other amino acid(s). The elongation can be used to enhance the stability or solubility of the peptides. 
         [0160]    Thus, the epitopes of the present invention may be identical to naturally occurring tumor-associated or tumor-specific epitopes or may include epitopes that differ by no more than four residues from the reference peptide, as long as they have substantially identical antigenic activity. 
         [0161]    In an alternative embodiment, the peptide is elongated on either or both sides by more than 4 amino acids, preferably to a total length of up to 30 amino acids. This may lead to MHC class II binding peptides. Binding to MHC class II can be tested by methods known in the art. 
         [0162]    Accordingly, the present invention provides peptides and variants of MHC class I epitopes, wherein the peptide or variant has an overall length of between 8 and 100, preferably between 8 and 30, and most preferred between 8 and 14, namely 8, 9, 10, 11, 12, 13, 14 amino acids, in case of the elongated class II binding peptides the length can also be 15, 16, 17, 18, 19, 20, 21 or 22 amino acids. 
         [0163]    Of course, the peptide or variant according to the present invention will have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class I or II. Binding of a peptide or a variant to a MHC complex may be tested by methods known in the art. 
         [0164]    Preferably, when the T cells specific for a peptide according to the present invention are tested against the substituted peptides, the peptide concentration at which the substituted peptides achieve half the maximal increase in lysis relative to background is no more than about 1 mM, preferably no more than about 1 μM, more preferably no more than about 1 nM, and still more preferably no more than about 100 pM, and most preferably no more than about 10 pM. It is also preferred that the substituted peptide be recognized by T cells from more than one individual, at least two, and more preferably three individuals. 
         [0165]    In a particularly preferred embodiment of the invention the peptide consists or consists essentially of an amino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 311. 
         [0166]    “Consisting essentially of” shall mean that a peptide according to the present invention, in addition to the sequence according to any of SEQ ID NO: 1 to SEQ ID NO 311 or a variant thereof contains additional N- and/or C-terminally located stretches of amino acids that are not necessarily forming part of the peptide that functions as an epitope for MHC molecules epitope. 
         [0167]    Nevertheless, these stretches can be important to provide an efficient introduction of the peptide according to the present invention into the cells. In one embodiment of the present invention, the peptide is part of a fusion protein which comprises, for example, the 80 N-terminal amino acids of the HLA-DR antigen-associated invariant chain (p33, in the following “Ii”) as derived from the NCBI, GenBank Accession number X00497. In other fusions, the peptides of the present invention can be fused to an antibody as described herein, or a functional part thereof, in particular into a sequence of an antibody, so as to be specifically targeted by said antibody, or, for example, to or into an antibody that is specific for dendritic cells as described herein. 
         [0168]    In addition, the peptide or variant may be modified further to improve stability and/or binding to MHC molecules in order to elicit a stronger immune response. Methods for such an optimization of a peptide sequence are well known in the art and include, for example, the introduction of reverse peptide bonds or non-peptide bonds. 
         [0169]    In a reverse peptide bond amino acid residues are not joined by peptide (—CO—NH—) linkages but the peptide bond is reversed. Such retro-inverso peptidomimetics may be made using methods known in the art, for example such as those described in Meziere et al (1997) (Meziere et al., 1997), incorporated herein by reference. This approach involves making pseudopeptides containing changes involving the backbone, and not the orientation of side chains. Meziere et al. (Meziere et al., 1997) show that for MHC binding and T helper cell responses, these pseudopeptides are useful. Retro-inverse peptides, which contain NH—CO bonds instead of CO—NH peptide bonds, are much more resistant to proteolysis. 
         [0170]    A non-peptide bond is, for example, —CH 2 —NH, —CH 2 S—, —CH 2 CH 2 —, —CH═CH—, —COCH 2 —, —CH(OH)CH 2 —, and —CH 2 SO—. U.S. Pat. No. 4,897,445 provides a method for the solid phase synthesis of non-peptide bonds (—CH 2 —NH) in polypeptide chains which involves polypeptides synthesized by standard procedures and the non-peptide bond synthesized by reacting an amino aldehyde and an amino acid in the presence of NaCNBH 3 . 
         [0171]    Peptides comprising the sequences described above may be synthesized with additional chemical groups present at their amino and/or carboxy termini, to enhance the stability, bioavailability, and/or affinity of the peptides. For example, hydrophobic groups such as carbobenzoxyl, dansyl, or t-butyloxycarbonyl groups may be added to the peptides&#39; amino termini. Likewise, an acetyl group or a 9-fluorenylmethoxy-carbonyl group may be placed at the peptides&#39; amino termini. Additionally, the hydrophobic group, t-butyloxycarbonyl, or an amido group may be added to the peptides&#39; carboxy termini. 
         [0172]    Further, the peptides of the invention may be synthesized to alter their steric configuration. For example, the D-isomer of one or more of the amino acid residues of the peptide may be used, rather than the usual L-isomer. Still further, at least one of the amino acid residues of the peptides of the invention may be substituted by one of the well-known non-naturally occurring amino acid residues. Alterations such as these may serve to increase the stability, bioavailability and/or binding action of the peptides of the invention. 
         [0173]    Similarly, a peptide or variant of the invention may be modified chemically by reacting specific amino acids either before or after synthesis of the peptide. Examples for such modifications are well known in the art and are summarized e.g. in R. Lundblad, Chemical Reagents for Protein Modification, 3rd ed. CRC Press, 2004 (Lundblad, 2004), which is incorporated herein by reference. Chemical modification of amino acids includes but is not limited to, modification by acylation, amidination, pyridoxylation of lysine, reductive alkylation, trinitrobenzylation of amino groups with 2,4,6-trinitrobenzene sulphonic acid (TNBS), amide modification of carboxyl groups and sulphydryl modification by performic acid oxidation of cysteine to cysteic acid, formation of mercurial derivatives, formation of mixed disulphides with other thiol compounds, reaction with maleimide, carboxymethylation with iodoacetic acid or iodoacetamide and carbamoylation with cyanate at alkaline pH, although without limitation thereto. In this regard, the skilled person is referred to Chapter 15 of Current Protocols In Protein Science, Eds. Coligan et al. (John Wiley and Sons NY 1995-2000) (Coligan et al., 1995) for more extensive methodology relating to chemical modification of proteins. 
         [0174]    Briefly, modification of e.g. arginyl residues in proteins is often based on the reaction of vicinal dicarbonyl compounds such as phenylglyoxal, 2,3-butanedione, and 1,2-cyclohexanedione to form an adduct. Another example is the reaction of methylglyoxal with arginine residues. Cysteine can be modified without concomitant modification of other nucleophilic sites such as lysine and histidine. As a result, a large number of reagents are available for the modification of cysteine. The websites of companies such as Sigma-Aldrich (www.sigma-aldrich.com) provide information on specific reagents. 
         [0175]    Selective reduction of disulfide bonds in proteins is also common. Disulfide bonds can be formed and oxidized during the heat treatment of biopharmaceuticals. Woodward&#39;s Reagent K may be used to modify specific glutamic acid residues. N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide can be used to form intra-molecular crosslinks between a lysine residue and a glutamic acid residue. For example, diethylpyrocarbonate is a reagent for the modification of histidyl residues in proteins. Histidine can also be modified using 4-hydroxy-2-nonenal. The reaction of lysine residues and other α-amino groups is, for example, useful in binding of peptides to surfaces or the cross-linking of proteins/peptides. Lysine is the site of attachment of poly(ethylene)glycol and the major site of modification in the glycosylation of proteins. Methionine residues in proteins can be modified with e.g. iodoacetamide, bromoethylamine, and chloramine T. 
         [0176]    Tetranitromethane and N-acetylimidazole can be used for the modification of tyrosyl residues. Cross-linking via the formation of dityrosine can be accomplished with hydrogen peroxide/copper ions. 
         [0177]    Recent studies on the modification of tryptophan have used N-bromosuccinimide, 2-hydroxy-5-nitrobenzyl bromide or 3-bromo-3-methyl-2-(2-nitrophenylmercapto)-3H-indole (BPNS-skatole). 
         [0178]    Successful modification of therapeutic proteins and peptides with PEG is often associated with an extension of circulatory half-life while cross-linking of proteins with glutaraldehyde, polyethylene glycol diacrylate and formaldehyde is used for the preparation of hydrogels. Chemical modification of allergens for immunotherapy is often achieved by carbamylation with potassium cyanate. 
         [0179]    A peptide or variant, wherein the peptide is modified or includes non-peptide bonds is a preferred embodiment of the invention. 
         [0180]    Another embodiment of the present invention relates to a non-naturally occurring peptide wherein said peptide consists or consists essentially of an amino acid sequence according to SEQ ID No: 1 to SEQ ID No: 311 and has been synthetically produced (e.g. synthesized) as a pharmaceutically acceptable salt. Methods to synthetically produce peptides are well known in the art. The salts of the peptides according to the present invention differ substantially from the peptides in their state(s) in vivo, as the peptides as generated in vivo are no salts. The non-natural salt form of the peptide mediates the solubility of the peptide, in particular in the context of pharmaceutical compositions comprising the peptides, e.g. the peptide vaccines as disclosed herein. A sufficient and at least substantial solubility of the peptide(s) is required in order to efficiently provide the peptides to the subject to be treated. Preferably, the salts are pharmaceutically acceptable salts of the peptides. These salts according to the invention include alkaline and earth alkaline salts such as salts of the Hofmeister series comprising as anions PO 4   3- , SO 4   2- , CH 3 COO − , Cl − , Br, NO 3 , ClO 4   − , I − , SCN −  and as cations NH 4   + , Rb + , K + , Na + , Cs + , Li + , Zn 2+ , Mg 2+ , Ca 2+ , Mn 2+ , Cu 2+  and Ba 2+ . Particularly salts are selected from (NH 4 ) 3 PO 4 , (NH 4 ) 2 HPO 4 , (NH 4 )H 2 PO 4 , (NH 4 ) 2 SO 4 , NH 4 CH 3 COO, NH 4 Cl, NH 4 Br, NH 4 NO 3 , NH 4 ClO 4 , NH 4 I, NH 4 SCN, Rb 3 PO 4 , Rb 2 HPO 4 , RbH 2 PO 4 , Rb 2 SO 4 , Rb 4 CH 3 COO, Rb 4 Cl, Rb 4 Br, Rb 4 NO 3 , Rb 4 ClO 4 , Rb 4 I, Rb 4 SCN, K 3 PO 4 , K 2 HPO 4 , KH 2 PO 4 , K 2 SO 4 , KCH 3 COO, KCl, KBr, KNO 3 , KClO 4 , KI, KSCN, Na 3 PO 4 , Na 2 HPO 4 , NaH 2 PO 4 , Na 2 SO 4 , NaCH 3 COO, NaCl, NaBr, NaNO 3 , NaClO 4 , NaI, NaSCN, ZnCl 2  Cs 3 PO 4 , Cs 2 HPO 4 , CsH 2 PO 4 , Cs 2 SO 4 , CsCH 3 COO, CsCl, CsBr, CsNO 3 , CsClO 4 , CsI, CsSCN, Li 3 PO 4 , Li 2 HPO 4 , LiH 2 PO 4 , Li 2 SO 4 , LiCH 3 COO, LiCl, LiBr, LiNO 3 , LiClO 4 , LiI, LiSCN, Cu 2 SO 4 , Mg 3 (PO 4 ) 2 , Mg 2 HPO 4 , Mg(H 2 PO 4 ) 2 , Mg 2 SO 4 , Mg(CH 3 COO) 2 , MgCl 2 , MgBr 2 , Mg(NO 3 ) 2 , Mg(ClO 4 ) 2 , MgI 2 , Mg(SCN) 2 , MnCl 2 , Ca 3 (PO 4 )Ca 2 HPO 4 , Ca(H 2 PO 4 ) 2 , CaSO 4 , Ca(CH 3 COO) 2 , CaCl 2 , CaBr 2 , Ca(NO 3 ) 2 , Ca(ClO 4 ) 2 , CaI 2 , Ca(SCN) 2 , Ba 3 (PO 4 ) 2 , Ba 2 HPO 4 , Ba(H 2 PO 4 ) 2 , BaSO 4 , Ba(CH 3 COO) 2 , BaCl 2 , BaBr 2 , Ba(NO 3 ) 2 , Ba(ClO 4 ) 2 , BaI 2 , and Ba(SCN) 2 . Particularly preferred are NH acetate, MgCl 2 , KH 2 PO 4 , Na 2 SO 4 , KCl, NaCl, and CaCl 2 , such as, for example, the chloride or acetate (trifluoroacetate) salts. 
         [0181]    Generally, peptides and variants (at least those containing peptide linkages between amino acid residues) may be synthesized by the Fmoc-polyamide mode of solid-phase peptide synthesis as disclosed by Lukas et al. (Lukas et al., 1981) and by references as cited therein. Temporary N-amino group protection is afforded by the 9-fluorenylmethyloxycarbonyl (Fmoc) group. Repetitive cleavage of this highly base-labile protecting group is done using 20% piperidine in N, N-dimethylformamide. Side-chain functionalities may be protected as their butyl ethers (in the case of serine threonine and tyrosine), butyl esters (in the case of glutamic acid and aspartic acid), butyloxycarbonyl derivative (in the case of lysine and histidine), trityl derivative (in the case of cysteine) and 4-methoxy-2,3,6-trimethylbenzenesulphonyl derivative (in the case of arginine). Where glutamine or asparagine are C-terminal residues, use is made of the 4,4′-dimethoxybenzhydryl group for protection of the side chain amido functionalities. The solid-phase support is based on a polydimethyl-acrylamide polymer constituted from the three monomers dimethylacrylamide (backbone-monomer), bisacryloylethylene diamine (cross linker) and acryloylsarcosine methyl ester (functionalizing agent). The peptide-to-resin cleavable linked agent used is the acid-labile 4-hydroxymethyl-phenoxyacetic acid derivative. All amino acid derivatives are added as their preformed symmetrical anhydride derivatives with the exception of asparagine and glutamine, which are added using a reversed N, N-dicyclohexyl-carbodiimide/1hydroxybenzotriazole mediated coupling procedure. All coupling and deprotection reactions are monitored using ninhydrin, trinitrobenzene sulphonic acid or isotin test procedures. Upon completion of synthesis, peptides are cleaved from the resin support with concomitant removal of side-chain protecting groups by treatment with 95% trifluoroacetic acid containing a 50% scavenger mix. Scavengers commonly used include ethanedithiol, phenol, anisole and water, the exact choice depending on the constituent amino acids of the peptide being synthesized. Also a combination of solid phase and solution phase methodologies for the synthesis of peptides is possible (see, for example, (Bruckdorfer et al., 2004), and the references as cited therein). 
         [0182]    Trifluoroacetic acid is removed by evaporation in vacuo, with subsequent trituration with diethyl ether affording the crude peptide. Any scavengers present are removed by a simple extraction procedure which on lyophilization of the aqueous phase affords the crude peptide free of scavengers. Reagents for peptide synthesis are generally available from e.g. Calbiochem-Novabiochem (Nottingham, UK). 
         [0183]    Purification may be performed by any one, or a combination of, techniques such as re-crystallization, size exclusion chromatography, ion-exchange chromatography, hydrophobic interaction chromatography and (usually) reverse-phase high performance liquid chromatography using e.g. acetonitrile/water gradient separation. 
         [0184]    Analysis of peptides may be carried out using thin layer chromatography, electrophoresis, in particular capillary electrophoresis, solid phase extraction (CSPE), reverse-phase high performance liquid chromatography, amino-acid analysis after acid hydrolysis and by fast atom bombardment (FAB) mass spectrometric analysis, as well as MALDI and ESI-Q-TOF mass spectrometric analysis. 
         [0185]    In order to select over-presented peptides, a presentation profile is calculated showing the median sample presentation as well as replicate variation. The profile juxtaposes samples of the tumor entity of interest to a baseline of normal tissue samples. Each of these profiles can then be consolidated into an over-presentation score by calculating the p-value of a Linear Mixed-Effects Model (Pinheiro et al., 2015) adjusting for multiple testing by False Discovery Rate (Benjamini and Hochberg, 1995) (cf. Example 1,  FIGS. 1A to 1P ). 
         [0186]    For the identification and relative quantitation of HLA ligands by mass spectrometry, HLA molecules from shock-frozen tissue samples were purified and HLA-associated peptides were isolated. The isolated peptides were separated and sequences were identified by online nano-electrospray-ionization (nanoESI) liquid chromatography-mass spectrometry (LC-MS) experiments. The resulting peptide sequences were verified by comparison of the fragmentation pattern of natural tumor-associated peptides (TUMAPs) recorded from NHL samples (N=18 A*02-positive samples) with the fragmentation patterns of corresponding synthetic reference peptides of identical sequences. Since the peptides were directly identified as ligands of HLA molecules of primary tumors, these results provide direct evidence for the natural processing and presentation of the identified peptides on primary cancer tissue obtained from 18 NHL patients. 
         [0187]    The discovery pipeline XPRESIDENT® v2.1 (see, for example, US 2013-0096016, which is hereby incorporated by reference in its entirety) allows the identification and selection of relevant over-presented peptide vaccine candidates based on direct relative quantitation of HLA-restricted peptide levels on cancer tissues in comparison to several different non-cancerous tissues and organs. This was achieved by the development of label-free differential quantitation using the acquired LC-MS data processed by a proprietary data analysis pipeline, combining algorithms for sequence identification, spectral clustering, ion counting, retention time alignment, charge state deconvolution and normalization. 
         [0188]    Presentation levels including error estimates for each peptide and sample were established. Peptides exclusively presented on tumor tissue and peptides over-presented in tumor versus non-cancerous tissues and organs have been identified. 
         [0189]    HLA-peptide complexes from NHL tissue samples were purified and HLA-associated peptides were isolated and analyzed by LC-MS (see examples). All TUMAPs contained in the present application were identified with this approach on primary NHL samples confirming their presentation on primary NHL. 
         [0190]    TUMAPs identified on multiple NHL and normal tissues were quantified using ion-counting of label-free LC-MS data. The method assumes that LC-MS signal areas of a peptide correlate with its abundance in the sample. All quantitative signals of a peptide in various LC-MS experiments were normalized based on central tendency, averaged per sample and merged into a bar plot, called presentation profile. The presentation profile consolidates different analysis methods like protein database search, spectral clustering, charge state deconvolution (decharging) and retention time alignment and normalization. 
         [0191]    Besides over-presentation of the peptide, mRNA expression of the underlying gene was tested. mRNA data were obtained via RNASeq analyses of normal tissues and cancer tissues (cf. Example 2,  FIGS. 2A-2C ). An additional source of normal tissue data was a database of publicly available RNA expression data from around 3000 normal tissue samples (Lonsdale, 2013). Peptides which are derived from proteins whose coding mRNA is highly expressed in cancer tissue, but very low or absent in vital normal tissues, were preferably included in the present invention. 
         [0192]    The present invention provides peptides that are useful in treating cancers/tumors, preferably NHL that over- or exclusively present the peptides of the invention. These peptides were shown by mass spectrometry to be naturally presented by HLA molecules on primary human NHL samples. 
         [0193]    Many of the source gene/proteins (also designated “full-length proteins” or “underlying proteins”) from which the peptides are derived were shown to be highly over-expressed in cancer compared with normal tissues—“normal tissues” in relation to this invention shall mean either healthy lymph node cells or other normal tissue cells, demonstrating a high degree of tumor association of the source genes (see Example 2). Moreover, the peptides themselves are strongly over-presented on tumor tissue—“tumor tissue” in relation to this invention shall mean a sample from a patient suffering from NHL, but not on normal tissues (see Example 1). 
         [0194]    HLA-bound peptides can be recognized by the immune system, specifically T lymphocytes. T cells can destroy the cells presenting the recognized HLA/peptide complex, e.g. NHL cells presenting the derived peptides. 
         [0195]    The peptides of the present invention have been shown to be capable of stimulating T cell responses and/or are over-presented and thus can be used for the production of antibodies and/or TCRs, such as soluble TCRs, according to the present invention (see Example 3, Example 4). Furthermore, the peptides when complexed with the respective MHC can be used for the production of antibodies and/or TCRs, in particular sTCRs, according to the present invention, as well. Respective methods are well known to the person of skill, and can be found in the respective literature as well. Thus, the peptides of the present invention are useful for generating an immune response in a patient by which tumor cells can be destroyed. An immune response in a patient can be induced by direct administration of the described peptides or suitable precursor substances (e.g. elongated peptides, proteins, or nucleic acids encoding these peptides) to the patient, ideally in combination with an agent enhancing the immunogenicity (i.e. an adjuvant). The immune response originating from such a therapeutic vaccination can be expected to be highly specific against tumor cells because the target peptides of the present invention are not presented on normal tissues in comparable copy numbers, preventing the risk of undesired autoimmune reactions against normal cells in the patient. 
         [0196]    The present description further relates to T-cell receptors (TCRs) comprising an alpha chain and a beta chain (“alpha/beta TCRs”). Also provided are peptides according to the invention capable of binding to TCRs and antibodies when presented by an MHC molecule. The present description also relates to nucleic acids, vectors and host cells for expressing TCRs and peptides of the present description; and methods of using the same. 
         [0197]    The term “T-cell receptor” (abbreviated TCR) refers to a heterodimeric molecule comprising an alpha polypeptide chain (alpha chain) and a beta polypeptide chain (beta chain), wherein the heterodimeric receptor is capable of binding to a peptide antigen presented by an HLA molecule. The term also includes so-called gamma/delta TCRs. 
         [0198]    In one embodiment the description provides a method of producing a TCR as described herein, the method comprising culturing a host cell capable of expressing the TCR under conditions suitable to promote expression of the TCR. 
         [0199]    The description in another aspect relates to methods according to the description, wherein the antigen is loaded onto class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or artificial antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell or the antigen is loaded onto class I or II MHC tetramers by tetramerizing the antigen/class I or II MHC complex monomers. 
         [0200]    The alpha and beta chains of alpha/beta TCR&#39;s, and the gamma and delta chains of gamma/delta TCRs, are generally regarded as each having two “domains”, namely variable and constant domains. The variable domain consists of a concatenation of variable region (V), and joining region (J). The variable domain may also include a leader region (L). Beta and delta chains may also include a diversity region (D). The alpha and beta constant domains may also include C-terminal transmembrane (TM) domains that anchor the alpha and beta chains to the cell membrane. 
         [0201]    With respect to gamma/delta TCRs, the term “TCR gamma variable domain” as used herein refers to the concatenation of the TCR gamma V (TRGV) region without leader region (L), and the TCR gamma J (TRGJ) region, and the term TCR gamma constant domain refers to the extracellular TRGC region, or to a C-terminal truncated TRGC sequence. Likewise the term “TCR delta variable domain” refers to the concatenation of the TCR delta V (TRDV) region without leader region (L) and the TCR delta D/J (TRDD/TRDJ) region, and the term “TCR delta constant domain” refers to the extracellular TRDC region, or to a C-terminal truncated TRDC sequence. 
         [0202]    TCRs of the present description preferably bind to an peptide-HLA molecule complex with a binding affinity (KD) of about 100 μM or less, about 50 μM or less, about 25 μM or less, or about 10 μM or less. More preferred are high affinity TCRs having binding affinities of about 1 μM or less, about 100 nM or less, about 50 nM or less, about 25 nM or less. Non-limiting examples of preferred binding affinity ranges for TCRs of the present invention include about 1 nM to about 10 nM; about 10 nM to about 20 nM; about 20 nM to about 30 nM; about 30 nM to about 40 nM; about 40 nM to about 50 nM; about 50 nM to about 60 nM; about 60 nM to about 70 nM; about 70 nM to about 80 nM; about 80 nM to about 90 nM; and about 90 nM to about 100 nM. 
         [0203]    As used herein in connect with TCRs of the present description, “specific binding” and grammatical variants thereof are used to mean a TCR having a binding affinity (KD) for a peptide-HLA molecule complex of 100 μM or less. 
         [0204]    Alpha/beta heterodimeric TCRs of the present description may have an introduced disulfide bond between their constant domains. Preferred TCRs of this type include those which have a TRAC constant domain sequence and a TRBC1 or TRBC2 constant domain sequence except that Thr 48 of TRAC and Ser 57 of TRBC1 or TRBC2 are replaced by cysteine residues, the said cysteines forming a disulfide bond between the TRAC constant domain sequence and the TRBC1 or TRBC2 constant domain sequence of the TCR. 
         [0205]    With or without the introduced inter-chain bond mentioned above, alpha/beta heterodimeric TCRs of the present description may have a TRAC constant domain sequence and a TRBC1 or TRBC2 constant domain sequence, and the TRAC constant domain sequence and the TRBC1 or TRBC2 constant domain sequence of the TCR may be linked by the native disulfide bond between Cys4 of exon 2 of TRAC and Cys2 of exon 2 of TRBC1 or TRBC2. 
         [0206]    TCRs of the present description may comprise a detectable label selected from the group consisting of a radionuclide, a fluorophore and biotin. TCRs of the present description may be conjugated to a therapeutically active agent, such as a radionuclide, a chemotherapeutic agent, or a toxin. 
         [0207]    In an embodiment, a TCR of the present description having at least one mutation in the alpha chain and/or having at least one mutation in the beta chain has modified glycosylation compared to the unmutated TCR. 
         [0208]    In an embodiment, a TCR comprising at least one mutation in the TCR alpha chain and/or TCR beta chain has a binding affinity for, and/or a binding half-life for, a peptide-HLA molecule complex, which is at least double that of a TCR comprising the unmutated TCR alpha chain and/or unmutated TCR beta chain. Affinity-enhancement of tumor-specific TCRs, and its exploitation, relies on the existence of a window for optimal TCR affinities. The existence of such a window is based on observations that TCRs specific for HLA-A2-restricted pathogens have KD values that are generally about 10-fold lower when compared to TCRs specific for HLA-A2-restricted tumor-associated self-antigens. It is now known, although tumor antigens have the potential to be immunogenic, because tumors arise from the individual&#39;s own cells only mutated proteins or proteins with altered translational processing will be seen as foreign by the immune system. Antigens that are upregulated or overexpressed (so called self-antigens) will not necessarily induce a functional immune response against the tumor: T-cells expressing TCRs that are highly reactive to these antigens will have been negatively selected within the thymus in a process known as central tolerance, meaning that only T-cells with low-affinity TCRs for self-antigens remain. Therefore, affinity of TCRs or variants of the present description to peptides can be enhanced by methods well known in the art. 
         [0209]    The present description further relates to a method of identifying and isolating a TCR according to the present description, said method comprising incubating PBMCs from HLA-A*02-negative healthy donors with A2/peptide monomers, incubating the PBMCs with tetramer-phycoerythrin (PE) and isolating the high avidity T-cells by fluo-rescence activated cell sorting (FACS)—Calibur analysis. 
         [0210]    The present description further relates to a method of identifying and isolating a TCR according to the present description, said method comprising obtaining a transgenic mouse with the entire human TCRαβ gene loci (1.1 and 0.7 Mb), whose T-cells express a diverse human TCR repertoire that compensates for mouse TCR deficiency, immunizing the mouse with a peptide, incubating PBMCs obtained from the transgenic mice with tetramer-phycoerythrin (PE), and isolating the high avidity T-cells by fluorescence activated cell sorting (FACS)—Calibur analysis. 
         [0211]    In one aspect, to obtain T-cells expressing TCRs of the present description, nucleic acids encoding TCR-alpha and/or TCR-beta chains of the present description are cloned into expression vectors, such as gamma retrovirus or lentivirus. The recombinant viruses are generated and then tested for functionality, such as antigen specificity and functional avidity. An aliquot of the final product is then used to transduce the target T-cell population (generally purified from patient PBMCs), which is expanded before infusion into the patient. 
         [0212]    In another aspect, to obtain T-cells expressing TCRs of the present description, TCR RNAs are synthesized by techniques known in the art, e.g., in vitro transcription sys-tems. The in vitro-synthesized TCR RNAs are then introduced into primary CD8+ T-cells obtained from healthy donors by electroporation to re-express tumor specific TCR-alpha and/or TCR-beta chains. 
         [0213]    To increase the expression, nucleic acids encoding TCRs of the present description may be operably linked to strong promoters, such as retroviral long terminal repeats (LTRs), cytomegalovirus (CMV), murine stem cell virus (MSCV) U3, phosphoglycerate kinase (PGK), β-actin, ubiquitin, and a simian virus 40 (SV40)/CD43 composite promoter, elongation factor (EF)-1a and the spleen focus-forming virus (SFFV) promoter. In a preferred embodiment, the promoter is heterologous to the nucleic acid being expressed. 
         [0214]    In addition to strong promoters, TCR expression cassettes of the present description may contain additional elements that can enhance transgene expression, including a central polypurine tract (cPPT), which promotes the nuclear translocation of lentiviral constructs (Follenzi et al., 2000), and the woodchuck hepatitis virus posttranscriptional regulatory element (wPRE), which increases the level of transgene expression by increasing RNA stability (Zufferey et al., 1999). 
         [0215]    The alpha and beta chains of a TCR of the present invention may be encoded by nucleic acids located in separate vectors, or may be encoded by polynucleotides located in the same vector. 
         [0216]    Achieving high-level TCR surface expression requires that both the TCR-alpha and TCR-beta chains of the introduced TCR be transcribed at high levels. To do so, the TCR-alpha and TCR-beta chains of the present description may be cloned into bi-cistronic constructs in a single vector, which has been shown to be capable of over-coming this obstacle. The use of a viral intraribosomal entry site (IRES) between the TCR-alpha and TCR-beta chains results in the coordinated expression of both chains, because the TCR-alpha and TCR-beta chains are generated from a single transcript that is broken into two proteins during translation, ensuring that an equal molar ratio of TCR-alpha and TCR-beta chains are produced. (Schmitt et al. 2009). 
         [0217]    Nucleic acids encoding TCRs of the present description may be codon optimized to increase expression from a host cell. Redundancy in the genetic code allows some amino acids to be encoded by more than one codon, but certain codons are less “op-timal” than others because of the relative availability of matching tRNAs as well as other factors (Gustafsson et al., 2004). Modifying the TCR-alpha and TCR-beta gene sequences such that each amino acid is encoded by the optimal codon for mammalian gene expression, as well as eliminating mRNA instability motifs or cryptic splice sites, has been shown to significantly enhance TCR-alpha and TCR-beta gene expression (Scholten et al., 2006). 
         [0218]    Furthermore, mispairing between the introduced and endogenous TCR chains may result in the acquisition of specificities that pose a significant risk for autoimmunity. For example, the formation of mixed TCR dimers may reduce the number of CD3 molecules available to form properly paired TCR complexes, and therefore can significantly decrease the functional avidity of the cells expressing the introduced TCR (Kuball et al., 2007). 
         [0219]    To reduce mispairing, the C-terminus domain of the introduced TCR chains of the present description may be modified in order to promote interchain affinity, while de-creasing the ability of the introduced chains to pair with the endogenous TCR. These strategies may include replacing the human TCR-alpha and TCR-beta C-terminus domains with their murine counterparts (murinized C-terminus domain); generating a second interchain disulfide bond in the C-terminus domain by introducing a second cysteine residue into both the TCR-alpha and TCR-beta chains of the introduced TCR (cysteine modification); swapping interacting residues in the TCR-alpha and TCR-beta chain C-terminus domains (“knob-in-hole”); and fusing the variable domains of the TCR-alpha and TCR-beta chains directly to CD3ζ (CD3ζ fusion). (Schmitt et al. 2009). 
         [0220]    In an embodiment, a host cell is engineered to express a TCR of the present description. In preferred embodiments, the host cell is a human T-cell or T-cell progenitor. In some embodiments the T-cell or T-cell progenitor is obtained from a cancer patient. In other embodiments the T-cell or T-cell progenitor is obtained from a healthy donor. Host cells of the present description can be allogeneic or autologous with respect to a patient to be treated. In one embodiment, the host is a gamma/delta T-cell transformed to express an alpha/beta TCR. 
         [0221]    A “pharmaceutical composition” is a composition suitable for administration to a human being in a medical setting. Preferably, a pharmaceutical composition is sterile and produced according to GMP guidelines. 
         [0222]    The pharmaceutical compositions comprise the peptides either in the free form or in the form of a pharmaceutically acceptable salt (see also above). As used herein, “a pharmaceutically acceptable salt” refers to a derivative of the disclosed peptides wherein the peptide is modified by making acid or base salts of the agent. For example, acid salts are prepared from the free base (typically wherein the neutral form of the drug has a neutral —NH2 group) involving reaction with a suitable acid. Suitable acids for preparing acid salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid phosphoric acid and the like. Conversely, preparation of basic salts of acid moieties which may be present on a peptide are prepared using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine or the like. 
         [0223]    In an especially preferred embodiment, the pharmaceutical compositions comprise the peptides as salts of acetic acid (acetates), trifluoro acetates or hydrochloric acid (chlorides). 
         [0224]    Preferably, the medicament of the present invention is an immunotherapeutic such as a vaccine. It may be administered directly into the patient, into the affected organ or systemically i.d., i.m., s.c., i.p. and i.v., or applied ex vivo to cells derived from the patient or a human cell line which are subsequently administered to the patient, or used in vitro to select a subpopulation of immune cells derived from the patient, which are then re-administered to the patient. If the nucleic acid is administered to cells in vitro, it may be useful for the cells to be transfected so as to co-express immune-stimulating cytokines, such as interleukin-2. The peptide may be substantially pure, or combined with an immune-stimulating adjuvant (see below) or used in combination with immune-stimulatory cytokines, or be administered with a suitable delivery system, for example liposomes. The peptide may also be conjugated to a suitable carrier such as keyhole limpet haemocyanin (KLH) or mannan (see WO 95/18145 and (Longenecker et al., 1993)). The peptide may also be tagged, may be a fusion protein, or may be a hybrid molecule. The peptides whose sequence is given in the present invention are expected to stimulate CD4 or CD8 T cells. However, stimulation of CD8 T cells is more efficient in the presence of help provided by CD4 T-helper cells. Thus, for MHC Class I epitopes that stimulate CD8 T cells the fusion partner or sections of a hybrid molecule suitably provide epitopes which stimulate CD4-positive T cells. CD4- and CD8-stimulating epitopes are well known in the art and include those identified in the present invention. 
         [0225]    In one aspect, the vaccine comprises at least one peptide having the amino acid sequence set forth SEQ ID No. 1 to SEQ ID No. 311, and at least one additional peptide, preferably two to 50, more preferably two to 25, even more preferably two to 20 and most preferably two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen or eighteen peptides. The peptide(s) may be derived from one or more specific TAAs and may bind to MHC class I molecules. 
         [0226]    A further aspect of the invention provides a nucleic acid (for example a polynucleotide) encoding a peptide or peptide variant of the invention. The polynucleotide may be, for example, DNA, cDNA, PNA, RNA or combinations thereof, either single- and/or double-stranded, or native or stabilized forms of polynucleotides, such as, for example, polynucleotides with a phosphorothioate backbone and it may or may not contain introns so long as it codes for the peptide. Of course, only peptides that contain naturally occurring amino acid residues joined by naturally occurring peptide bonds are encodable by a polynucleotide. A still further aspect of the invention provides an expression vector capable of expressing a polypeptide according to the invention. 
         [0227]    A variety of methods have been developed to link polynucleotides, especially DNA, to vectors for example via complementary cohesive termini. For instance, complementary homopolymer tracts can be added to the DNA segment to be inserted to the vector DNA. The vector and DNA segment are then joined by hydrogen bonding between the complementary homopolymeric tails to form recombinant DNA molecules. 
         [0228]    Synthetic linkers containing one or more restriction sites provide an alternative method of joining the DNA segment to vectors. Synthetic linkers containing a variety of restriction endonuclease sites are commercially available from a number of sources including International Biotechnologies Inc. New Haven, Conn., USA. 
         [0229]    A desirable method of modifying the DNA encoding the polypeptide of the invention employs the polymerase chain reaction as disclosed by Saiki R K, et al. (Saiki et al., 1988). This method may be used for introducing the DNA into a suitable vector, for example by engineering in suitable restriction sites, or it may be used to modify the DNA in other useful ways as is known in the art. If viral vectors are used, pox- or adenovirus vectors are preferred. 
         [0230]    The DNA (or in the case of retroviral vectors, RNA) may then be expressed in a suitable host to produce a polypeptide comprising the peptide or variant of the invention. Thus, the DNA encoding the peptide or variant of the invention may be used in accordance with known techniques, appropriately modified in view of the teachings contained herein, to construct an expression vector, which is then used to transform an appropriate host cell for the expression and production of the polypeptide of the invention. Such techniques include those disclosed, for example, in U.S. Pat. Nos. 4,440,859, 4,530,901, 4,582,800, 4,677,063, 4,678,751, 4,704,362, 4,710,463, 4,757,006, 4,766,075, and 4,810,648. 
         [0231]    The DNA (or in the case of retroviral vectors, RNA) encoding the polypeptide constituting the compound of the invention may be joined to a wide variety of other DNA sequences for introduction into an appropriate host. The companion DNA will depend upon the nature of the host, the manner of the introduction of the DNA into the host, and whether episomal maintenance or integration is desired. 
         [0232]    Generally, the DNA is inserted into an expression vector, such as a plasmid, in proper orientation and correct reading frame for expression. If necessary, the DNA may be linked to the appropriate transcriptional and translational regulatory control nucleotide sequences recognized by the desired host, although such controls are generally available in the expression vector. The vector is then introduced into the host through standard techniques. Generally, not all of the hosts will be transformed by the vector. Therefore, it will be necessary to select for transformed host cells. One selection technique involves incorporating into the expression vector a DNA sequence, with any necessary control elements, that codes for a selectable trait in the transformed cell, such as antibiotic resistance. 
         [0233]    Alternatively, the gene for such selectable trait can be on another vector, which is used to co-transform the desired host cell. 
         [0234]    Host cells that have been transformed by the recombinant DNA of the invention are then cultured for a sufficient time and under appropriate conditions known to those skilled in the art in view of the teachings disclosed herein to permit the expression of the polypeptide, which can then be recovered. 
         [0235]    Many expression systems are known, including bacteria (for example  E. coli  and  Bacillus subtilis ), yeasts (for example  Saccharomyces cerevisiae ), filamentous fungi (for example  Aspergillus  spec.), plant cells, animal cells and insect cells. Preferably, the system can be mammalian cells such as CHO cells available from the ATCC Cell Biology Collection. 
         [0236]    A typical mammalian cell vector plasmid for constitutive expression comprises the CMV or SV40 promoter with a suitable poly A tail and a resistance marker, such as neomycin. One example is pSVL available from Pharmacia, Piscataway, N.J., USA. An example of an inducible mammalian expression vector is pMSG, also available from Pharmacia. Useful yeast plasmid vectors are pRS403-406 and pRS413-416 and are generally available from Stratagene Cloning Systems, La Jolla, Calif. 92037, USA. Plasmids pRS403, pRS404, pRS405 and pRS406 are Yeast Integrating plasmids (Ylps) and incorporate the yeast selectable markers HIS3, TRP1, LEU2 and URA3. Plasmids pRS413-416 are Yeast Centromere plasmids (Ycps). CMV promoter-based vectors (for example from Sigma-Aldrich) provide transient or stable expression, cytoplasmic expression or secretion, and N-terminal or C-terminal tagging in various combinations of FLAG, 3×FLAG, c-myc or MAT. These fusion proteins allow for detection, purification and analysis of recombinant protein. Dual-tagged fusions provide flexibility in detection. 
         [0237]    The strong human cytomegalovirus (CMV) promoter regulatory region drives constitutive protein expression levels as high as 1 mg/L in COS cells. For less potent cell lines, protein levels are typically ˜0.1 mg/L. The presence of the SV40 replication origin will result in high levels of DNA replication in SV40 replication permissive COS cells. CMV vectors, for example, can contain the pMB1 (derivative of pBR322) origin for replication in bacterial cells, the b-lactamase gene for ampicillin resistance selection in bacteria, hGH polyA, and the f1 origin. Vectors containing the pre-pro-trypsin leader (PPT) sequence can direct the secretion of FLAG fusion proteins into the culture medium for purification using ANTI-FLAG antibodies, resins, and plates. Other vectors and expression systems are well known in the art for use with a variety of host cells. 
         [0238]    In another embodiment two or more peptides or peptide variants of the invention are encoded and thus expressed in a successive order (similar to “beads on a string” constructs). In doing so, the peptides or peptide variants may be linked or fused together by stretches of linker amino acids, such as for example LLLLLL, or may be linked without any additional peptide(s) between them. These constructs can also be used for cancer therapy, and may induce immune responses both involving MHC I and MHC II. 
         [0239]    The present invention also relates to a host cell transformed with a polynucleotide vector construct of the present invention. The host cell can be either prokaryotic or eukaryotic. Bacterial cells may be preferred prokaryotic host cells in some circumstances and typically are a strain of  E. coli  such as, for example, the  E. coli  strains DH5 available from Bethesda Research Laboratories Inc., Bethesda, Md., USA, and RR1 available from the American Type Culture Collection (ATCC) of Rockville, Md., USA (No ATCC 31343). Preferred eukaryotic host cells include yeast, insect and mammalian cells, preferably vertebrate cells such as those from a mouse, rat, monkey or human fibroblastic and colon cell lines. Yeast host cells include YPH499, YPH500 and YPH501, which are generally available from Stratagene Cloning Systems, La Jolla, Calif. 92037, USA. Preferred mammalian host cells include Chinese hamster ovary (CHO) cells available from the ATCC as CCL61, NIH Swiss mouse embryo cells NIH/3T3 available from the ATCC as CRL 1658, monkey kidney-derived COS-1 cells available from the ATCC as CRL 1650 and 293 cells which are human embryonic kidney cells. Preferred insect cells are Sf9 cells which can be transfected with baculovirus expression vectors. An overview regarding the choice of suitable host cells for expression can be found in, for example, the textbook of Paulina Balbás and Argelia Lorence “Methods in Molecular Biology Recombinant Gene Expression, Reviews and Protocols,” Part One, Second Edition, ISBN 978-1-58829-262-9, and other literature known to the person of skill. 
         [0240]    Transformation of appropriate cell hosts with a DNA construct of the present invention is accomplished by well-known methods that typically depend on the type of vector used. With regard to transformation of prokaryotic host cells, see, for example, Cohen et al. (Cohen et al., 1972) and (Green and Sambrook, 2012). Transformation of yeast cells is described in Sherman et al. (Sherman et al., 1986). The method of Beggs (Beggs, 1978) is also useful. With regard to vertebrate cells, reagents useful in transfecting such cells, for example calcium phosphate and DEAE-dextran or liposome formulations, are available from Stratagene Cloning Systems, or Life Technologies Inc., Gaithersburg, Md. 20877, USA. Electroporation is also useful for transforming and/or transfecting cells and is well known in the art for transforming yeast cell, bacterial cells, insect cells and vertebrate cells. 
         [0241]    Successfully transformed cells, i.e. cells that contain a DNA construct of the present invention, can be identified by well-known techniques such as PCR. Alternatively, the presence of the protein in the supernatant can be detected using antibodies. 
         [0242]    It will be appreciated that certain host cells of the invention are useful in the preparation of the peptides of the invention, for example bacterial, yeast and insect cells. However, other host cells may be useful in certain therapeutic methods. For example, antigen-presenting cells, such as dendritic cells, may usefully be used to express the peptides of the invention such that they may be loaded into appropriate MHC molecules. Thus, the current invention provides a host cell comprising a nucleic acid or an expression vector according to the invention. 
         [0243]    In a preferred embodiment, the host cell is an antigen presenting cell, in particular a dendritic cell or antigen presenting cell. APCs loaded with a recombinant fusion protein containing prostatic acid phosphatase (PAP) were approved by the U.S. Food and Drug Administration (FDA) on Apr. 29, 2010, to treat asymptomatic or minimally symptomatic metastatic HRPC (Sipuleucel-T) (Rini et al., 2006; Small et al., 2006). 
         [0244]    A further aspect of the invention provides a method of producing a peptide or its variant, the method comprising culturing a host cell and isolating the peptide from the host cell or its culture medium. 
         [0245]    In another embodiment, the peptide, the nucleic acid or the expression vector of the invention are used in medicine. For example, the peptide or its variant may be prepared for intravenous (i.v.) injection, sub-cutaneous (s.c.) injection, intradermal (i.d.) injection, intraperitoneal (i.p.) injection, intramuscular (i.m.) injection. Preferred methods of peptide injection include s.c., i.d., i.p., i.m., and i.v. Preferred methods of DNA injection include i.d., i.m., s.c., i.p. and i.v. Doses of e.g. between 50 μg and 1.5 mg, preferably 125 μg to 500 μg, of peptide or DNA may be given and will depend on the respective peptide or DNA. Dosages of this range were successfully used in previous trials (Walter et al., 2012). 
         [0246]    The polynucleotide used for active vaccination may be substantially pure, or contained in a suitable vector or delivery system. The nucleic acid may be DNA, cDNA, PNA, RNA or a combination thereof. Methods for designing and introducing such a nucleic acid are well known in the art. An overview is provided by e.g. Teufel et al. (Teufel et al., 2005). Polynucleotide vaccines are easy to prepare, but the mode of action of these vectors in inducing an immune response is not fully understood. Suitable vectors and delivery systems include viral DNA and/or RNA, such as systems based on adenovirus, vaccinia virus, retroviruses, herpes virus, adeno-associated virus or hybrids containing elements of more than one virus. Non-viral delivery systems include cationic lipids and cationic polymers and are well known in the art of DNA delivery. Physical delivery, such as via a “gene-gun” may also be used. The peptide or peptides encoded by the nucleic acid may be a fusion protein, for example with an epitope that stimulates T cells for the respective opposite CDR as noted above. 
         [0247]    The medicament of the invention may also include one or more adjuvants. Adjuvants are substances that non-specifically enhance or potentiate the immune response (e.g., immune responses mediated by CD8-positive T cells and helper-T (TH) cells to an antigen, and would thus be considered useful in the medicament of the present invention. Suitable adjuvants include, but are not limited to, 1018 ISS, aluminum salts, AMPLIVAX®, AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, flagellin or TLRS ligands derived from flagellin, FLT3 ligand, GM-CSF, IC30, IC31, Imiquimod (ALDARA®), resiquimod, ImuFact IMP321, Interleukins as IL-2, IL-13, IL-21, Interferon-alpha or -beta, or pegylated derivatives thereof, IS Patch, ISS, ISCOMATRIX, ISCOMs, JuvImmune®, LipoVac, MALP2, MF59, monophosphoryl lipid A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, water-in-oil and oil-in-water emulsions, OK-432, OM-174, OM-197-MP-EC, ONTAK, OspA, PepTel® vector system, poly(lactid co-glycolid) [PLG]-based and dextran microparticles, talactoferrin SRL172, Virosomes and other Virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, Aquila&#39;s QS21 stimulon, which is derived from saponin, mycobacterial extracts and synthetic bacterial cell wall mimics, and other proprietary adjuvants such as Ribi&#39;s Detox, Quil, or Superfos. Adjuvants such as Freund&#39;s or GM-CSF are preferred. Several immunological adjuvants (e.g., MF59) specific for dendritic cells and their preparation have been described previously (Allison and Krummel, 1995). Also cytokines may be used. Several cytokines have been directly linked to influencing dendritic cell migration to lymphoid tissues (e.g., TNF-), accelerating the maturation of dendritic cells into efficient antigen-presenting cells for T-lymphocytes (e.g., GM-CSF, IL-1 and IL-4) (U.S. Pat. No. 5,849,589, specifically incorporated herein by reference in its entirety) and acting as immunoadjuvants (e.g., IL-12, IL-15, IL-23, IL-7, IFN-alpha. IFN-beta) (Gabrilovich et al., 1996). 
         [0248]    CpG immunostimulatory oligonucleotides have also been reported to enhance the effects of adjuvants in a vaccine setting. Without being bound by theory, CpG oligonucleotides act by activating the innate (non-adaptive) immune system via Toll-like receptors (TLR), mainly TLR9. CpG triggered TLR9 activation enhances antigen-specific humoral and cellular responses to a wide variety of antigens, including peptide or protein antigens, live or killed viruses, dendritic cell vaccines, autologous cellular vaccines and polysaccharide conjugates in both prophylactic and therapeutic vaccines. More importantly it enhances dendritic cell maturation and differentiation, resulting in enhanced activation of TH1 cells and strong cytotoxic T-lymphocyte (CTL) generation, even in the absence of CD4 T cell help. The TH1 bias induced by TLR9 stimulation is maintained even in the presence of vaccine adjuvants such as alum or incomplete Freund&#39;s adjuvant (IFA) that normally promote a TH2 bias. CpG oligonucleotides show even greater adjuvant activity when formulated or co-administered with other adjuvants or in formulations such as microparticles, nanoparticles, lipid emulsions or similar formulations, which are especially necessary for inducing a strong response when the antigen is relatively weak. They also accelerate the immune response and enable the antigen doses to be reduced by approximately two orders of magnitude, with comparable antibody responses to the full-dose vaccine without CpG in some experiments (Krieg, 2006). U.S. Pat. No. 6,406,705 B1 describes the combined use of CpG oligonucleotides, non-nucleic acid adjuvants and an antigen to induce an antigen-specific immune response. A CpG TLR9 antagonist is dSLIM (double Stem Loop Immunomodulator) by Mologen (Berlin, Germany) which is a preferred component of the pharmaceutical composition of the present invention. Other TLR binding molecules such as RNA binding TLR 7, TLR 8 and/or TLR 9 may also be used. 
         [0249]    Other examples for useful adjuvants include, but are not limited to chemically modified CpGs (e.g. CpR, Idera), dsRNA analogues such as Poly(I:C) and derivates thereof (e.g. AmpliGen®, Hiltonol®, poly-(ICLC), poly(IC-R), poly(I:C12U), non-CpG bacterial DNA or RNA as well as immunoactive small molecules and antibodies such as cyclophosphamide, sunitinib, Bevacizumab®, celebrex, NCX-4016, sildenafil, tadalafil, vardenafil, sorafenib, temozolomide, temsirolimus, XL-999, CP-547632, pazopanib, VEGF Trap, ZD2171, AZD2171, anti-CTLA4, other antibodies targeting key structures of the immune system (e.g. anti-CD40, anti-TGFbeta, anti-TNFalpha receptor) and SC58175, which may act therapeutically and/or as an adjuvant. The amounts and concentrations of adjuvants and additives useful in the context of the present invention can readily be determined by the skilled artisan without undue experimentation. 
         [0250]    Preferred adjuvants are anti-CD40, imiquimod, resiquimod, GM-CSF, cyclophosphamide, sunitinib, bevacizumab, interferon-alpha, CpG oligonucleotides and derivates, poly-(I:C) and derivates, RNA, sildenafil, and particulate formulations with PLG or virosomes. 
         [0251]    In a preferred embodiment, the pharmaceutical composition according to the invention the adjuvant is selected from the group consisting of colony-stimulating factors, such as Granulocyte Macrophage Colony Stimulating Factor (GM-CSF, sargramostim), cyclophosphamide, imiquimod, resiquimod, and interferon-alpha. 
         [0252]    In a preferred embodiment, the pharmaceutical composition according to the invention the adjuvant is selected from the group consisting of colony-stimulating factors, such as Granulocyte Macrophage Colony Stimulating Factor (GM-CSF, sargramostim), cyclophosphamide, imiquimod and resiquimod. In a preferred embodiment of the pharmaceutical composition according to the invention, the adjuvant is cyclophosphamide, imiquimod or resiquimod. Even more preferred adjuvants are Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, poly-ICLC (Hiltonol®) and anti-CD40 mAB, or combinations thereof. 
         [0253]    This composition is used for parenteral administration, such as subcutaneous, intradermal, intramuscular or oral administration. For this, the peptides and optionally other molecules are dissolved or suspended in a pharmaceutically acceptable, preferably aqueous carrier. 
         [0254]    In addition, the composition can contain excipients, such as buffers, binding agents, blasting agents, diluents, flavors, lubricants, etc. The peptides can also be administered together with immune stimulating substances, such as cytokines. An extensive listing of excipients that can be used in such a composition, can be, for example, taken from A. Kibbe, Handbook of Pharmaceutical Excipients (Kibbe, 2000). The composition can be used for a prevention, prophylaxis and/or therapy of adenomatous or cancerous diseases. Exemplary formulations can be found in, for example, EP2112253. 
         [0255]    It is important to realize that the immune response triggered by the vaccine according to the invention attacks the cancer in different cell-stages and different stages of development. Furthermore, different cancer associated signaling pathways are attacked. This is an advantage over vaccines that address only one or few targets, which may cause the tumor to easily adapt to the attack (tumor escape). Furthermore, not all individual tumors express the same pattern of antigens. Therefore, a combination of several tumor-associated peptides ensures that every single tumor bears at least some of the targets. The composition is designed in such a way that each tumor is expected to express several of the antigens and cover several independent pathways necessary for tumor growth and maintenance. Thus, the vaccine can easily be used “off-the-shelf” for a larger patient population. This means that a pre-selection of patients to be treated with the vaccine can be restricted to HLA typing, does not require any additional biomarker assessments for antigen expression, but it is still ensured that several targets are simultaneously attacked by the induced immune response, which is important for efficacy (Banchereau et al., 2001; Walter et al., 2012). 
         [0256]    As used herein, the term “scaffold” refers to a molecule that specifically binds to an (e.g. antigenic) determinant. In one embodiment, a scaffold is able to direct the entity to which it is attached (e.g. a (second) antigen binding moiety) to a target site, for example to a specific type of tumor cell or tumor stroma bearing the antigenic determinant (e.g. the complex of a peptide with MHC, according to the application at hand). In another embodiment a scaffold is able to activate signaling through its target antigen, for example a T cell receptor complex antigen. Scaffolds include but are not limited to antibodies and fragments thereof, antigen binding domains of an antibody, comprising an antibody heavy chain variable region and an antibody light chain variable region, binding proteins comprising at least one Ankyrin repeat motif and single domain antigen binding (SDAB) molecules, aptamers, (soluble) TCRs and (modified) cells such as allogenic or autologous T cells. To assess whether a molecule is a scaffold binding to a target, binding assays can be performed. 
         [0257]    “Specific” binding means that the scaffold binds the peptide-MHC-complex of interest better than other naturally occurring peptide-MHC-complexes, to an extent that a scaffold armed with an active molecule that is able to kill a cell bearing the specific target is not able to kill another cell without the specific target but presenting other peptide-MHC complex(es). Binding to other peptide-MHC complexes is irrelevant if the peptide of the cross-reactive peptide-MHC is not naturally occurring, i.e. not derived from the human HLA-peptidome. Tests to assess target cell killing are well known in the art. They should be performed using target cells (primary cells or cell lines) with unaltered peptide-MHC presentation, or cells loaded with peptides such that naturally occurring peptide-MHC levels are reached. 
         [0258]    Each scaffold can comprise a labelling which provides that the bound scaffold can be detected by determining the presence or absence of a signal provided by the label. For example, the scaffold can be labelled with a fluorescent dye or any other applicable cellular marker molecule. Such marker molecules are well known in the art. For example, a fluorescence-labelling, for example provided by a fluorescence dye, can provide a visualization of the bound aptamer by fluorescence or laser scanning microscopy or flow cytometry. Each scaffold can be conjugated with a second active molecule such as for example IL-21, anti-CD3, and anti-CD28. For further information on polypeptide scaffolds see for example the background section of WO 2014/071978A1 and the references cited therein. 
         [0259]    The present invention further relates to aptamers. Aptamers (see for example WO 2014/191359 and the literature as cited therein) are short single-stranded nucleic acid molecules, which can fold into defined three-dimensional structures and recognize specific target structures. They have appeared to be suitable alternatives for developing targeted therapies. Aptamers have been shown to selectively bind to a variety of complex targets with high affinity and specificity. 
         [0260]    Aptamers recognizing cell surface located molecules have been identified within the past decade and provide means for developing diagnostic and therapeutic approaches. Since aptamers have been shown to possess almost no toxicity and immunogenicity they are promising candidates for biomedical applications. Indeed aptamers, for example prostate-specific membrane-antigen recognizing aptamers, have been successfully employed for targeted therapies and shown to be functional in xenograft in vivo models. Furthermore, aptamers recognizing specific tumor cell lines have been identified. 
         [0261]    DNA aptamers can be selected to reveal broad-spectrum recognition properties for various cancer cells, and particularly those derived from solid tumors, while non-tumorigenic and primary healthy cells are not recognized. If the identified aptamers recognize not only a specific tumor sub-type but rather interact with a series of tumors, this renders the aptamers applicable as so-called broad-spectrum diagnostics and therapeutics. 
         [0262]    Further, investigation of cell-binding behavior with flow cytometry showed that the aptamers revealed very good apparent affinities that are within the nanomolar range. 
         [0263]    Aptamers are useful for diagnostic and therapeutic purposes. Further, it could be shown that some of the aptamers are taken up by tumor cells and thus can function as molecular vehicles for the targeted delivery of anti-cancer agents such as siRNA into tumor cells. 
         [0264]    Aptamers can be selected against complex targets such as cells and tissues and complexes of the peptides comprising, preferably consisting of, a sequence according to any of SEQ ID NO 1 to SEQ ID NO 311, according to the present invention with the MHC molecule, using the cell-SELEX (Systematic Evolution of Ligands by Exponential enrichment) technique. 
         [0265]    The peptides of the present invention can be used to generate and develop specific antibodies against MHC/peptide complexes. These can be used for therapy, targeting toxins or radioactive substances to the diseased tissue. Another use of these antibodies can be targeting radionuclides to the diseased tissue for imaging purposes such as PET. This use can help to detect small metastases or to determine the size and precise localization of diseased tissues. 
         [0266]    Therefore, it is a further aspect of the invention to provide a method for producing a recombinant antibody specifically binding to a human major histocompatibility complex (MHC) class I or II being complexed with a HLA-restricted antigen, the method comprising: immunizing a genetically engineered non-human mammal comprising cells expressing said human major histocompatibility complex (MHC) class I or II with a soluble form of a MHC class I or II molecule being complexed with said HLA-restricted antigen; isolating mRNA molecules from antibody producing cells of said non-human mammal; producing a phage display library displaying protein molecules encoded by said mRNA molecules; and isolating at least one phage from said phage display library, said at least one phage displaying said antibody specifically binding to said human major histocompatibility complex (MHC) class I or II being complexed with said HLA-restricted antigen. 
         [0267]    It is a further aspect of the invention to provide an antibody that specifically binds to a human major histocompatibility complex (MHC) class I or II being complexed with a HLA-restricted antigen, wherein the antibody preferably is a polyclonal antibody, monoclonal antibody, bi-specific antibody and/or a chimeric antibody. 
         [0268]    Respective methods for producing such antibodies and single chain class I major histocompatibility complexes, as well as other tools for the production of these antibodies are disclosed in WO 03/068201, WO 2004/084798, WO 01/72768, WO 03/070752, and in publications (Cohen et al., 2003a; Cohen et al., 2003b; Denkberg et al., 2003), which for the purposes of the present invention are all explicitly incorporated by reference in their entireties. 
         [0269]    Preferably, the antibody is binding with a binding affinity of below 20 nanomolar, preferably of below 10 nanomolar, to the complex, which is also regarded as “specific” in the context of the present invention. 
         [0270]    The present invention relates to a peptide comprising a sequence that is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 311, or a variant thereof which is at least 88% homologous (preferably identical) to SEQ ID NO: 1 to SEQ ID NO: 311 or a variant thereof that induces T cells cross-reacting with said peptide, wherein said peptide is not the underlying full-length polypeptide. 
         [0271]    The present invention further relates to a peptide comprising a sequence that is selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 311 or a variant thereof which is at least 88% homologous (preferably identical) to SEQ ID NO: 1 to SEQ ID NO: 311, wherein said peptide or variant has an overall length of between 8 and 100, preferably between 8 and 30, and most preferred between 8 and 14 amino acids. 
         [0272]    The present invention further relates to the peptides according to the invention that have the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or -II. 
         [0273]    The present invention further relates to the peptides according to the invention wherein the peptide consists or consists essentially of an amino acid sequence according to SEQ ID NO: 1 to SEQ ID NO: 311. 
         [0274]    The present invention further relates to the peptides according to the invention, wherein the peptide is (chemically) modified and/or includes non-peptide bonds. 
         [0275]    The present invention further relates to the peptides according to the invention, wherein the peptide is part of a fusion protein, in particular comprising N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii), or wherein the peptide is fused to (or into) an antibody, such as, for example, an antibody that is specific for dendritic cells. 
         [0276]    The present invention further relates to a nucleic acid, encoding the peptides according to the invention, provided that the peptide is not the complete (full) human protein. 
         [0277]    The present invention further relates to the nucleic acid according to the invention that is DNA, cDNA, PNA, RNA or combinations thereof. 
         [0278]    The present invention further relates to an expression vector capable of expressing a nucleic acid according to the present invention. 
         [0279]    The present invention further relates to a peptide according to the present invention, a nucleic acid according to the present invention or an expression vector according to the present invention for use in medicine, in particular in the treatment of NHL. 
         [0280]    The present invention further relates to a host cell comprising a nucleic acid according to the invention or an expression vector according to the invention. 
         [0281]    The present invention further relates to the host cell according to the present invention that is an antigen presenting cell, and preferably a dendritic cell. 
         [0282]    The present invention further relates to a method of producing a peptide according to the present invention, said method comprising culturing the host cell according to the present invention, and isolating the peptide from said host cell or its culture medium. 
         [0283]    The present invention further relates to the method according to the present invention, where-in the antigen is loaded onto class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell. 
         [0284]    The present invention further relates to the method according to the invention, wherein the antigen-presenting cell comprises an expression vector capable of expressing said peptide containing SEQ ID NO: 1 to SEQ ID NO: 311 or said variant amino acid sequence. 
         [0285]    The present invention further relates to activated T cells, produced by the method according to the present invention, wherein said T cells selectively recognizes a cell which aberrantly expresses a polypeptide comprising an amino acid sequence according to the present invention. 
         [0286]    The present invention further relates to a method of killing target cells in a patient which target cells aberrantly express a polypeptide comprising any amino acid sequence according to the present invention, the method comprising administering to the patient an effective number of T cells as according to the present invention. 
         [0287]    The present invention further relates to the use of any peptide described, a nucleic acid according to the present invention, an expression vector according to the present invention, a cell according to the present invention, or an activated cytotoxic T lymphocyte according to the present invention as a medicament or in the manufacture of a medicament. The present invention further relates to a use according to the present invention, wherein the medicament is active against cancer. 
         [0288]    The present invention further relates to a use according to the invention, wherein the medicament is a vaccine. The present invention further relates to a use according to the invention, wherein the medicament is active against cancer. 
         [0289]    The present invention further relates to a use according to the invention, wherein said cancer cells are NHL cells or other solid or hematological tumor cells such as non-small cell lung cancer, small cell lung cancer, renal cell cancer, brain cancer, gastric cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, leukemia, breast cancer, melanoma, ovarian cancer, urinary bladder cancer, uterine cancer, gallbladder and bile duct cancer. 
         [0290]    The present invention further relates to particular marker proteins and biomarkers based on the peptides according to the present invention, herein called “targets” that can be used in the diagnosis and/or prognosis of NHL. The present invention also relates to the use of these novel targets for cancer treatment. 
         [0291]    The term “antibody” or “antibodies” is used herein in a broad sense and includes both polyclonal and monoclonal antibodies. In addition to intact or “full” immunoglobulin molecules, also included in the term “antibodies” are fragments (e.g. CDRs, Fv, Fab and Fc fragments) or polymers of those immunoglobulin molecules and humanized versions of immunoglobulin molecules, as long as they exhibit any of the desired properties (e.g., specific binding of a NHL marker (poly)peptide, delivery of a toxin to a NHL cell expressing a cancer marker gene at an increased level, and/or inhibiting the activity of a NHL marker polypeptide) according to the invention. 
         [0292]    Whenever possible, the antibodies of the invention may be purchased from commercial sources. The antibodies of the invention may also be generated using well-known methods. The skilled artisan will understand that either full length NHL marker polypeptides or fragments thereof may be used to generate the antibodies of the invention. A polypeptide to be used for generating an antibody of the invention may be partially or fully purified from a natural source, or may be produced using recombinant DNA techniques. 
         [0293]    For example, a cDNA encoding a peptide according to the present invention, such as a peptide according to SEQ ID NO: 1 to SEQ ID NO: 311 polypeptide, or a variant or fragment thereof, can be expressed in prokaryotic cells (e.g., bacteria) or eukaryotic cells (e.g., yeast, insect, or mammalian cells), after which the recombinant protein can be purified and used to generate a monoclonal or polyclonal antibody preparation that specifically bind the NHL marker polypeptide used to generate the antibody according to the invention. 
         [0294]    One of skill in the art will realize that the generation of two or more different sets of monoclonal or polyclonal antibodies maximizes the likelihood of obtaining an antibody with the specificity and affinity required for its intended use (e.g., ELISA, immunohistochemistry, in vivo imaging, immunotoxin therapy). The antibodies are tested for their desired activity by known methods, in accordance with the purpose for which the antibodies are to be used (e.g., ELISA, immunohistochemistry, immunotherapy, etc.; for further guidance on the generation and testing of antibodies, see, e.g., Greenfield, 2014 (Greenfield, 2014)). For example, the antibodies may be tested in ELISA assays or, Western blots, immunohistochemical staining of formalin-fixed cancers or frozen tissue sections. After their initial in vitro characterization, antibodies intended for therapeutic or in vivo diagnostic use are tested according to known clinical testing methods. 
         [0295]    The term “monoclonal antibody” as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e.; the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. The monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired antagonistic activity (U.S. Pat. No. 4,816,567, which is hereby incorporated in its entirety). 
         [0296]    Monoclonal antibodies of the invention may be prepared using hybridoma methods. In a hybridoma method, a mouse or other appropriate host animal is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vitro. 
         [0297]    The monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). 
         [0298]    In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly Fab fragments, can be accomplished using routine techniques known in the art. For instance, digestion can be performed using papain. Examples of papain digestion are described in WO 94/29348 and U.S. Pat. No. 4,342,566. Papain digestion of antibodies typically produces two identical antigen binding fragments, called Fab fragments, each with a single antigen binding site, and a residual Fc fragment. Pepsin treatment yields a F(ab′)2 fragment and a pFc′ fragment. 
         [0299]    The antibody fragments, whether attached to other sequences or not, can also include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the fragment is not significantly altered or impaired compared to the non-modified antibody or antibody fragment. These modifications can provide for some additional property, such as to remove/add amino acids capable of disulfide bonding, to increase its bio-longevity, to alter its secretory characteristics, etc. In any case, the antibody fragment must possess a bioactive property, such as binding activity, regulation of binding at the binding domain, etc. Functional or active regions of the antibody may be identified by mutagenesis of a specific region of the protein, followed by expression and testing of the expressed polypeptide. Such methods are readily apparent to a skilled practitioner in the art and can include site-specific mutagenesis of the nucleic acid encoding the antibody fragment. 
         [0300]    The antibodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′ or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. 
         [0301]    Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Humanization can be essentially performed by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such “humanized” antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. 
         [0302]    Transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production can be employed. For example, it has been described that the homozygous deletion of the antibody heavy chain joining region gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice will result in the production of human antibodies upon antigen challenge. Human antibodies can also be produced in phage display libraries. 
         [0303]    Antibodies of the invention are preferably administered to a subject in a pharmaceutically acceptable carrier. Typically, an appropriate amount of a pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Examples of the pharmaceutically-acceptable carrier include saline, Ringer&#39;s solution and dextrose solution. The pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of antibody being administered. 
         [0304]    The antibodies can be administered to the subject, patient, or cell by injection (e.g., intravenous, intraperitoneal, subcutaneous, intramuscular), or by other methods such as infusion that ensure its delivery to the bloodstream in an effective form. The antibodies may also be administered by intratumoral or peritumoral routes, to exert local as well as systemic therapeutic effects. Local or intravenous injection is preferred. 
         [0305]    Effective dosages and schedules for administering the antibodies may be determined empirically, and making such determinations is within the skill in the art. Those skilled in the art will understand that the dosage of antibodies that must be administered will vary depending on, for example, the subject that will receive the antibody, the route of administration, the particular type of antibody used and other drugs being administered. A typical daily dosage of the antibody used alone might range from about 1 (μg/kg to up to 100 mg/kg of body weight or more per day, depending on the factors mentioned above. Following administration of an antibody, preferably for treating NHL, the efficacy of the therapeutic antibody can be assessed in various ways well known to the skilled practitioner. 
         [0306]    For instance, the size, number, and/or distribution of cancer in a subject receiving treatment may be monitored using standard tumor imaging techniques. A therapeutically-administered antibody that arrests tumor growth, results in tumor shrinkage, and/or prevents the development of new tumors, compared to the disease course that would occurs in the absence of antibody administration, is an efficacious antibody for treatment of cancer. 
         [0307]    It is a further aspect of the invention to provide a method for producing a soluble T-cell receptor (sTCR) recognizing a specific peptide-MHC complex. Such soluble T-cell receptors can be generated from specific T-cell clones, and their affinity can be increased by mutagenesis targeting the complementarity-determining regions. For the purpose of T-cell receptor selection, phage display can be used (US 2010/0113300, (Liddy et al., 2012)). For the purpose of stabilization of T-cell receptors during phage display and in case of practical use as drug, alpha and beta chain can be linked e.g. by non-native disulfide bonds, other covalent bonds (single-chain T-cell receptor), or by dimerization domains (Boulter et al., 2003; Card et al., 2004; Willcox et al., 1999). The T-cell receptor can be linked to toxins, drugs, cytokines (see, for example, US 2013/0115191), and domains recruiting effector cells such as an anti-CD3 domain, etc., in order to execute particular functions on target cells. Moreover, it could be expressed in T cells used for adoptive transfer. Further information can be found in WO 2004/033685A1 and WO 2004/074322A1. A combination of sTCRs is described in WO 2012/056407A1. Additional methods for the production are disclosed in WO 2013/057586A1. 
         [0308]    In addition, the peptides and/or the TCRs or antibodies or other binding molecules of the present invention can be used to verify a pathologist&#39;s diagnosis of a cancer based on a biopsied sample. 
         [0309]    The antibodies or TCRs may also be used for in vivo diagnostic assays. Generally, the antibody is labeled with a radionucleotide (such as  111 In,  99 Tc,  14 C,  131 I,  3 H,  32 P or  35 S)) so that the tumor can be localized using immunoscintiography. In one embodiment, antibodies or fragments thereof bind to the extracellular domains of two or more targets of a protein selected from the group consisting of the above-mentioned proteins, and the affinity value (Kd) is less than 1×10 μM. 
         [0310]    Antibodies for diagnostic use may be labeled with probes suitable for detection by various imaging methods. Methods for detection of probes include, but are not limited to, fluorescence, light, confocal and electron microscopy; magnetic resonance imaging and spectroscopy; fluoroscopy, computed tomography and positron emission tomography. Suitable probes include, but are not limited to, fluorescein, rhodamine, eosin and other fluorophores, radioisotopes, gold, gadolinium and other lanthanides, paramagnetic iron, fluorine-18 and other positron-emitting radionuclides. Additionally, probes may be bi- or multi-functional and be detectable by more than one of the methods listed. These antibodies may be directly or indirectly labeled with said probes. Attachment of probes to the antibodies includes covalent attachment of the probe, incorporation of the probe into the antibody, and the covalent attachment of a chelating compound for binding of probe, amongst others well recognized in the art. For immunohistochemistry, the disease tissue sample may be fresh or frozen or may be embedded in paraffin and fixed with a preservative such as formalin. The fixed or embedded section contains the sample are contacted with a labeled primary antibody and secondary antibody, wherein the antibody is used to detect the expression of the proteins in situ. 
         [0311]    Another aspect of the present invention includes an in vitro method for producing activated T cells, the method comprising contacting in vitro T cells with antigen loaded human MHC molecules expressed on the surface of a suitable antigen-presenting cell for a period of time sufficient to activate the T cell in an antigen specific manner, wherein the antigen is a peptide according to the invention. Preferably a sufficient amount of the antigen is used with an antigen-presenting cell. 
         [0312]    Preferably the mammalian cell lacks or has a reduced level or function of the TAP peptide transporter. Suitable cells that lack the TAP peptide transporter include T2, RMA-S and  Drosophila  cells. TAP is the transporter associated with antigen processing. 
         [0313]    The human peptide loading deficient cell line T2 is available from the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Md. 20852, USA under Catalogue No CRL 1992; the  Drosophila  cell line Schneider line 2 is available from the ATCC under Catalogue No CRL 19863; the mouse RMA-S cell line is described in Ljunggren et al. (Ljunggren and Karre, 1985). 
         [0314]    Preferably, before transfection the host cell expresses substantially no MHC class I molecules. It is also preferred that the stimulator cell expresses a molecule important for providing a co-stimulatory signal for T-cells such as any of B7.1, B7.2, ICAM-1 and LFA 3. The nucleic acid sequences of numerous MHC class I molecules and of the co-stimulator molecules are publicly available from the GenBank and EMBL databases. 
         [0315]    In case of a MHC class I epitope being used as an antigen, the T cells are CD8-positive T cells. 
         [0316]    If an antigen-presenting cell is transfected to express such an epitope, preferably the cell comprises an expression vector capable of expressing a peptide containing SEQ ID NO: 1 to SEQ ID NO: 311, or a variant amino acid sequence thereof. 
         [0317]    A number of other methods may be used for generating T cells in vitro. For example, autologous tumor-infiltrating lymphocytes can be used in the generation of CTL. Plebanski et al. (Plebanski et al., 1995) made use of autologous peripheral blood lymphocytes (PLBs) in the preparation of T cells. Furthermore, the production of autologous T cells by pulsing dendritic cells with peptide or polypeptide, or via infection with recombinant virus is possible. Also, B cells can be used in the production of autologous T cells. In addition, macrophages pulsed with peptide or polypeptide, or infected with recombinant virus, may be used in the preparation of autologous T cells. S. Walter et al. (Walter et al., 2003) describe the in vitro priming of T cells by using artificial antigen presenting cells (aAPCs), which is also a suitable way for generating T cells against the peptide of choice. In the present invention, aAPCs were generated by the coupling of preformed MHC:peptide complexes to the surface of polystyrene particles (microbeads) by biotin:streptavidin biochemistry. This system permits the exact control of the MHC density on aAPCs, which allows to selectively eliciting high- or low-avidity antigen-specific T cell responses with high efficiency from blood samples. Apart from MHC:peptide complexes, aAPCs should carry other proteins with co-stimulatory activity like anti-CD28 antibodies coupled to their surface. Furthermore, such aAPC-based systems often require the addition of appropriate soluble factors, e. g. cytokines, like interleukin-12. 
         [0318]    Allogeneic cells may also be used in the preparation of T cells and a method is described in detail in WO 97/26328, incorporated herein by reference. For example, in addition to  Drosophila  cells and T2 cells, other cells may be used to present antigens such as CHO cells, baculovirus-infected insect cells, bacteria, yeast, and vaccinia-infected target cells. In addition plant viruses may be used (see, for example, Porta et al. (Porta et al., 1994) which describes the development of cowpea mosaic virus as a high-yielding system for the presentation of foreign peptides. 
         [0319]    The activated T cells that are directed against the peptides of the invention are useful in therapy. Thus, a further aspect of the invention provides activated T cells obtainable by the foregoing methods of the invention. 
         [0320]    Activated T cells, which are produced by the above method, will selectively recognize a cell that aberrantly expresses a polypeptide that comprises an amino acid sequence of SEQ ID NO: 1 to SEQ ID NO 311. 
         [0321]    Preferably, the T cell recognizes the cell by interacting through its TCR with the HLA/peptide-complex (for example, binding). The T cells are useful in a method of killing target cells in a patient whose target cells aberrantly express a polypeptide comprising an amino acid sequence of the invention wherein the patient is administered an effective number of the activated T cells. The T cells that are administered to the patient may be derived from the patient and activated as described above (i.e. they are autologous T cells). Alternatively, the T cells are not from the patient but are from another individual. Of course, it is preferred if the individual is a healthy individual. By “healthy individual” the inventors mean that the individual is generally in good health, preferably has a competent immune system and, more preferably, is not suffering from any disease that can be readily tested for, and detected. 
         [0322]    In vivo, the target cells for the CD8-positive T cells according to the present invention can be cells of the tumor (which sometimes express MHC class II) and/or stromal cells surrounding the tumor (tumor cells) (which sometimes also express MHC class II; (Dengjel et al., 2006)). 
         [0323]    The T cells of the present invention may be used as active ingredients of a therapeutic composition. Thus, the invention also provides a method of killing target cells in a patient whose target cells aberrantly express a polypeptide comprising an amino acid sequence of the invention, the method comprising administering to the patient an effective number of T cells as defined above. 
         [0324]    By “aberrantly expressed” the inventors also mean that the polypeptide is over-expressed compared to levels of expression in normal tissues or that the gene is silent in the tissue from which the tumor is derived but in the tumor it is expressed. By “over-expressed” the inventors mean that the polypeptide is present at a level at least 1.2-fold of that present in normal tissue; preferably at least 2-fold, and more preferably at least 5-fold or 10-fold the level present in normal tissue. 
         [0325]    T cells may be obtained by methods known in the art, e.g. those described above. 
         [0326]    Protocols for this so-called adoptive transfer of T cells are well known in the art. Reviews can be found in: Gattioni et al. and Morgan et al. (Gattinoni et al., 2006; Morgan et al., 2006). 
         [0327]    Another aspect of the present invention includes the use of the peptides complexed with MHC to generate a T-cell receptor whose nucleic acid is cloned and is introduced into a host cell, preferably a T cell. This engineered T cell can then be transferred to a patient for therapy of cancer. 
         [0328]    Any molecule of the invention, i.e. the peptide, nucleic acid, antibody, expression vector, cell, activated T cell, T-cell receptor or the nucleic acid encoding it, is useful for the treatment of disorders, characterized by cells escaping an immune response. Therefore, any molecule of the present invention may be used as medicament or in the manufacture of a medicament. The molecule may be used by itself or combined with other molecule(s) of the invention or (a) known molecule(s). 
         [0329]    The present invention is further directed at a kit comprising: 
         [0000]    (a) a container containing a pharmaceutical composition as described above, in solution or in lyophilized form;
 
(b) optionally a second container containing a diluent or reconstituting solution for the lyophilized formulation; and
 
(c) optionally, instructions for (i) use of the solution or (ii) reconstitution and/or use of the lyophilized formulation.
 
         [0330]    The kit may further comprise one or more of (iii) a buffer, (iv) a diluent, (v) a filter, (vi) a needle, or (v) a syringe. The container is preferably a bottle, a vial, a syringe or test tube; and it may be a multi-use container. The pharmaceutical composition is preferably lyophilized. 
         [0331]    Kits of the present invention preferably comprise a lyophilized formulation of the present invention in a suitable container and instructions for its reconstitution and/or use. Suitable containers include, for example, bottles, vials (e.g. dual chamber vials), syringes (such as dual chamber syringes) and test tubes. The container may be formed from a variety of materials such as glass or plastic. Preferably the kit and/or container contain/s instructions on or associated with the container that indicates directions for reconstitution and/or use. For example, the label may indicate that the lyophilized formulation is to be reconstituted to peptide concentrations as described above. The label may further indicate that the formulation is useful or intended for subcutaneous administration. 
         [0332]    The container holding the formulation may be a multi-use vial, which allows for repeat administrations (e.g., from 2-6 administrations) of the reconstituted formulation. The kit may further comprise a second container comprising a suitable diluent (e.g., sodium bicarbonate solution). 
         [0333]    Upon mixing of the diluent and the lyophilized formulation, the final peptide concentration in the reconstituted formulation is preferably at least 0.15 mg/mL/peptide (=75 μg) and preferably not more than 3 mg/mL/peptide (=1500 μg). The kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. 
         [0334]    Kits of the present invention may have a single container that contains the formulation of the pharmaceutical compositions according to the present invention with or without other components (e.g., other compounds or pharmaceutical compositions of these other compounds) or may have distinct container for each component. 
         [0335]    Preferably, kits of the invention include a formulation of the invention packaged for use in combination with the co-administration of a second compound (such as adjuvants (e.g. GM-CSF), a chemotherapeutic agent, a natural product, a hormone or antagonist, an anti-angiogenesis agent or inhibitor, an apoptosis-inducing agent or a chelator) or a pharmaceutical composition thereof. The components of the kit may be pre-complexed or each component may be in a separate distinct container prior to administration to a patient. The components of the kit may be provided in one or more liquid solutions, preferably, an aqueous solution, more preferably, a sterile aqueous solution. The components of the kit may also be provided as solids, which may be converted into liquids by addition of suitable solvents, which are preferably provided in another distinct container. 
         [0336]    The container of a therapeutic kit may be a vial, test tube, flask, bottle, syringe, or any other means of enclosing a solid or liquid. Usually, when there is more than one component, the kit will contain a second vial or other container, which allows for separate dosing. The kit may also contain another container for a pharmaceutically acceptable liquid. Preferably, a therapeutic kit will contain an apparatus (e.g., one or more needles, syringes, eye droppers, pipette, etc.), which enables administration of the agents of the invention that are components of the present kit. 
         [0337]    The present formulation is one that is suitable for administration of the peptides by any acceptable route such as oral (enteral), nasal, ophthal, subcutaneous, intradermal, intramuscular, intravenous or transdermal. Preferably, the administration is s.c., and most preferably i.d. administration may be by infusion pump. 
         [0338]    Since the peptides of the invention were isolated from NHL, the medicament of the invention is preferably used to treat NHL. 
         [0339]    The present invention further relates to a method for producing a personalized pharmaceutical (composition) for an individual patient comprising manufacturing a pharmaceutical composition comprising at least one peptide selected from a warehouse of pre-screened TUMAPs, wherein the at least one peptide used in the pharmaceutical composition is selected for suitability in the individual patient. In one embodiment, the pharmaceutical composition is a vaccine. The method could also be adapted to produce T cell clones for down-stream applications, such as TCR isolations, or soluble antibodies, and other treatment options. 
         [0340]    A “personalized pharmaceutical” shall mean specifically tailored therapies for one individual patient that will only be used for therapy in such individual patient, including actively personalized cancer vaccines and adoptive cellular therapies using autologous patient tissue. 
         [0341]    As used herein, the term “warehouse” shall refer to a group or set of peptides that have been pre-screened for immunogenicity and/or over-presentation in a particular tumor type. The term “warehouse” is not intended to imply that the particular peptides included in the vaccine have been pre-manufactured and stored in a physical facility, although that possibility is contemplated. It is expressly contemplated that the peptides may be manufactured de novo for each individualized vaccine produced, or may be pre-manufactured and stored. The warehouse (e.g. in the form of a database) is composed of tumor-associated peptides which were highly overexpressed in the tumor tissue of NHL patients with various HLA-A HLA-B and HLA-C alleles. It may contain MHC class I and MHC class II peptides or elongated MHC class I peptides. In addition to the tumor associated peptides collected from several NHL tissues, the warehouse may contain HLA-A*02 and HLA-A*24 marker peptides. These peptides allow comparison of the magnitude of T-cell immunity induced by TUMAPS in a quantitative manner and hence allow important conclusion to be drawn on the capacity of the vaccine to elicit anti-tumor responses. Secondly, they function as important positive control peptides derived from a “non-self” antigen in the case that any vaccine-induced T-cell responses to TUMAPs derived from “self” antigens in a patient are not observed. And thirdly, it may allow conclusions to be drawn, regarding the status of immunocompetence of the patient. 
         [0342]    TUMAPs for the warehouse are identified by using an integrated functional genomics approach combining gene expression analysis, mass spectrometry, and T-cell immunology (XPresident®). The approach assures that only TUMAPs truly present on a high percentage of tumors but not or only minimally expressed on normal tissue, are chosen for further analysis. For initial peptide selection, NHL samples from patients and blood from healthy donors were analyzed in a stepwise approach: 
         [0000]    1. HLA ligands from the malignant material were identified by mass spectrometry
 
2. Genome-wide messenger ribonucleic acid (mRNA) expression analysis was used to identify genes over-expressed in the malignant tissue (NHL) compared with a range of normal organs and tissues
 
3. Identified HLA ligands were compared to gene expression data. Peptides over-presented or selectively presented on tumor tissue, preferably encoded by selectively expressed or over-expressed genes as detected in step 2 were considered suitable TUMAP candidates for a multi-peptide vaccine.
 
4. Literature research was performed in order to identify additional evidence supporting the relevance of the identified peptides as TUMAPs
 
5. The relevance of over-expression at the mRNA level was confirmed by redetection of selected TUMAPs from step 3 on tumor tissue and lack of (or infrequent) detection on healthy tissues.
 
6. In order to assess, whether an induction of in vivo T-cell responses by the selected peptides may be feasible, in vitro immunogenicity assays were performed using human T cells from healthy donors as well as from NHL patients.
 
         [0343]    In an aspect, the peptides are pre-screened for immunogenicity before being included in the warehouse. By way of example, and not limitation, the immunogenicity of the peptides included in the warehouse is determined by a method comprising in vitro T-cell priming through repeated stimulations of CD8+ T cells from healthy donors with artificial antigen presenting cells loaded with peptide/MHC complexes and anti-CD28 antibody. 
         [0344]    This method is preferred for rare cancers and patients with a rare expression profile. In contrast to multi-peptide cocktails with a fixed composition as currently developed, the warehouse allows a significantly higher matching of the actual expression of antigens in the tumor with the vaccine. Selected single or combinations of several “off-the-shelf” peptides will be used for each patient in a multitarget approach. In theory, an approach based on selection of e.g. 5 different antigenic peptides from a library of 50 would already lead to approximately 17 million possible drug product (DP) compositions. 
         [0345]    In an aspect, the peptides are selected for inclusion in the vaccine based on their suitability for the individual patient based on the method according to the present invention as described herein, or as below. 
         [0346]    The HLA phenotype, transcriptomic and peptidomic data is gathered from the patient&#39;s tumor material, and blood samples to identify the most suitable peptides for each patient containing “warehouse” and patient-unique (i.e. mutated) TUMAPs. Those peptides will be chosen, which are selectively or over-expressed in the patients&#39; tumor and, where possible, show strong in vitro immunogenicity if tested with the patients&#39; individual PBMCs. 
         [0347]    Preferably, the peptides included in the vaccine are identified by a method comprising: (a) identifying tumor-associated peptides (TUMAPs) presented by a tumor sample from the individual patient; (b) comparing the peptides identified in (a) with a warehouse (database) of peptides as described above; and (c) selecting at least one peptide from the warehouse (database) that correlates with a tumor-associated peptide identified in the patient. For example, the TUMAPs presented by the tumor sample are identified by: (a1) comparing expression data from the tumor sample to expression data from a sample of normal tissue corresponding to the tissue type of the tumor sample to identify proteins that are over-expressed or aberrantly expressed in the tumor sample; and (a2) correlating the expression data with sequences of MHC ligands bound to MHC class I and/or class II molecules in the tumor sample to identify MHC ligands derived from proteins over-expressed or aberrantly expressed by the tumor. Preferably, the sequences of MHC ligands are identified by eluting bound peptides from MHC molecules isolated from the tumor sample, and sequencing the eluted ligands. Preferably, the tumor sample and the normal tissue are obtained from the same patient. 
         [0348]    In addition to, or as an alternative to, selecting peptides using a warehousing (database) model, TUMAPs may be identified in the patient de novo, and then included in the vaccine. As one example, candidate TUMAPs may be identified in the patient by (a1) comparing expression data from the tumor sample to expression data from a sample of normal tissue corresponding to the tissue type of the tumor sample to identify proteins that are over-expressed or aberrantly expressed in the tumor sample; and (a2) correlating the expression data with sequences of MHC ligands bound to MHC class I and/or class II molecules in the tumor sample to identify MHC ligands derived from proteins over-expressed or aberrantly expressed by the tumor. As another example, proteins may be identified containing mutations that are unique to the tumor sample relative to normal corresponding tissue from the individual patient, and TUMAPs can be identified that specifically target the mutation. 
         [0349]    For example, the genome of the tumor and of corresponding normal tissue can be sequenced by whole genome sequencing: For discovery of non-synonymous mutations in the protein-coding regions of genes, genomic DNA and RNA are extracted from tumor tissues and normal non-mutated genomic germline DNA is extracted from peripheral blood mononuclear cells (PBMCs). The applied NGS approach is confined to the re-sequencing of protein coding regions (exome re-sequencing). For this purpose, exonic DNA from human samples is captured using vendor-supplied target enrichment kits, followed by sequencing with e.g. a HiSeq2000 (Illumina). Additionally, tumor mRNA is sequenced for direct quantification of gene expression and validation that mutated genes are expressed in the patients&#39; tumors. The resultant millions of sequence reads are processed through software algorithms. The output list contains mutations and gene expression. Tumor-specific somatic mutations are determined by comparison with the PBMC-derived germline variations and prioritized. The de novo identified peptides can then be tested for immunogenicity as described above for the warehouse, and candidate TUMAPs possessing suitable immunogenicity are selected for inclusion in the vaccine. 
         [0350]    In one exemplary embodiment, the peptides included in the vaccine are identified by: (a) identifying tumor-associated peptides (TUMAPs) presented by a tumor sample from the individual patient by the method as described above; (b) comparing the peptides identified in a) with a warehouse of peptides that have been prescreened for immunogenicity and overpresentation in tumors as compared to corresponding normal tissue; (c) selecting at least one peptide from the warehouse that correlates with a tumor-associated peptide identified in the patient; and (d) optionally, selecting at least one peptide identified de novo in (a) confirming its immunogenicity. 
         [0351]    In one exemplary embodiment, the peptides included in the vaccine are identified by: (a) identifying tumor-associated peptides (TUMAPs) presented by a tumor sample from the individual patient; and (b) selecting at least one peptide identified de novo in (a) and confirming its immunogenicity. 
         [0352]    Once the peptides for a personalized peptide based vaccine are selected, the vaccine is produced. The vaccine preferably is a liquid formulation consisting of the individual peptides dissolved in between 20-40% DMSO, preferably about 30-35% DMSO, such as about 33% DMSO. 
         [0353]    Each peptide to be included into a product is dissolved in DMSO. The concentration of the single peptide solutions has to be chosen depending on the number of peptides to be included into the product. The single peptide-DMSO solutions are mixed in equal parts to achieve a solution containing all peptides to be included in the product with a concentration of ˜2.5 mg/ml per peptide. The mixed solution is then diluted 1:3 with water for injection to achieve a concentration of 0.826 mg/ml per peptide in 33% DMSO. The diluted solution is filtered through a 0.22 μm sterile filter. The final bulk solution is obtained. 
         [0354]    Final bulk solution is filled into vials and stored at −20° C. until use. One vial contains 700 μL solution, containing 0.578 mg of each peptide. Of this, 500 μL (approx. 400 μg per peptide) will be applied for intradermal injection. 
         [0355]    In addition to being useful for treating cancer, the peptides of the present invention are also useful as diagnostics. Since the peptides were generated from NHL cells and since it was determined that these peptides are not or at lower levels present in normal tissues, these peptides can be used to diagnose the presence of a cancer. 
         [0356]    The presence of claimed peptides on tissue biopsies in blood samples can assist a pathologist in diagnosis of cancer. Detection of certain peptides by means of antibodies, mass spectrometry or other methods known in the art can tell the pathologist that the tissue sample is malignant or inflamed or generally diseased, or can be used as a biomarker for NHL. Presence of groups of peptides can enable classification or sub-classification of diseased tissues. 
         [0357]    The detection of peptides on diseased tissue specimen can enable the decision about the benefit of therapies involving the immune system, especially if T-lymphocytes are known or expected to be involved in the mechanism of action. Loss of MHC expression is a well described mechanism by which infected of malignant cells escape immuno-surveillance. Thus, presence of peptides shows that this mechanism is not exploited by the analyzed cells. 
         [0358]    The peptides of the present invention might be used to analyze lymphocyte responses against those peptides such as T cell responses or antibody responses against the peptide or the peptide complexed to MHC molecules. These lymphocyte responses can be used as prognostic markers for decision on further therapy steps. These responses can also be used as surrogate response markers in immunotherapy approaches aiming to induce lymphocyte responses by different means, e.g. vaccination of protein, nucleic acids, autologous materials, adoptive transfer of lymphocytes. In gene therapy settings, lymphocyte responses against peptides can be considered in the assessment of side effects. Monitoring of lymphocyte responses might also be a valuable tool for follow-up examinations of transplantation therapies, e.g. for the detection of graft versus host and host versus graft diseases. 
         [0359]    The present invention will now be described in the following examples which describe preferred embodiments thereof, and with reference to the accompanying figures, nevertheless, without being limited thereto. For the purposes of the present invention, all references as cited herein are incorporated by reference in their entireties. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0360]    The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. 
           [0361]      FIGS. 1A to 1P  show the over-presentation of various peptides in normal tissues (white bars) and NHL (black bars).  FIG. 1A ) Gene symbol: TOX2, Peptide: LLSGQLPTI (SEQ ID NO.: 1); Tissues from left to right: 3 adipose tissues, 3 adrenal glands, 15 blood cell samples, 12 blood vessels, 10 bone marrows, 7 brains, 8 breasts, 2 cartilages, 2 eyes, 3 gallbladders, 6 hearts, 14 kidneys, 19 large intestines, 20 livers, 45 lungs, 8 lymph nodes, 7 nerves, 3 ovaries, 10 pancreases, 3 parathyroid glands, 1 peritoneum, 5 pituitary glands, 6 placentas, 3 pleuras, 3 prostates, 7 salivary glands, 5 skeletal muscles, 11 skins, 3 small intestines, 11 spleens, 5 stomachs, 6 testes, 2 thymi, 2 thyroid glands, 9 tracheas, 7 ureters, 8 urinary bladders, 5 uteri, 6 esophagi, 18 NHL samples. The peptide has additionally been detected on 1/84 lung cancers, 1/17 chronic lymphocytic leukemias, 1/20 pancreatic cancer cell lines, 1/20 ovarian cancers and 1/16 uterus cancers.  FIG. 1B ) Gene symbol: TAP1, Peptide: VLQGLTFTL (SEQ ID NO.: 5); Tissues from left to right: 3 adipose tissues, 3 adrenal glands, 15 blood cell samples, 12 blood vessels, 10 bone marrows, 7 brains, 8 breasts, 2 cartilages, 2 eyes, 3 gallbladders, 6 hearts, 14 kidneys, 19 large intestines, 20 livers, 45 lungs, 8 lymph nodes, 7 nerves, 3 ovaries, 10 pancreases, 3 parathyroid glands, 1 peritoneum, 5 pituitary glands, 6 placentas, 3 pleuras, 3 prostates, 7 salivary glands, 5 skeletal muscles, 11 skins, 3 small intestines, 11 spleens, 5 stomachs, 6 testes, 2 thymi, 2 thyroid glands, 9 tracheas, 7 ureters, 8 urinary bladders, 5 uteri, 6 esophagi, 18 NHL samples. The peptide has additionally been detected on 4/101 lung cancers, 1/18 breast cancers, 1/17 chronic lymphocytic leukemias, 2/17 bile duct and gallbladder cancers, 2/16 melanomas, 2/20 ovarian cancers and 1/15 urinary bladder cancers.  FIG. 1C ) Gene symbol: SLC20A1, Peptide: ILASIFETV (SEQ ID NO.: 41); Tissues from left to right: 3 adipose tissues, 3 adrenal glands, 15 blood cell samples, 12 blood vessels, 10 bone marrows, 7 brains, 8 breasts, 2 cartilages, 2 eyes, 3 gallbladders, 6 hearts, 14 kidneys, 19 large intestines, 20 livers, 45 lungs, 8 lymph nodes, 7 nerves, 3 ovaries, 10 pancreases, 3 parathyroid glands, 1 peritoneum, 5 pituitary glands, 6 placentas, 3 pleuras, 3 prostates, 7 salivary glands, 5 skeletal muscles, 11 skins, 3 small intestines, 11 spleens, 5 stomachs, 6 testes, 2 thymi, 2 thyroid glands, 9 tracheas, 7 ureters, 8 urinary bladders, 5 uteri, 6 esophagi, 18 NHL samples. The peptide has additionally been detected on 10/101 lung cancers, 4/18 acute myelogenous leukemias, 1/18 breast cancers, 1/17 chronic lymphocytic leukemias, 3/20 pancreatic cancer cell lines, 2/17 bile duct and gallbladder cancers, 4/16 melanomas, 1/20 ovarian cancers, 2/19 pancreas cancers, 1/38 prostate cancers, 2/22 kidney cancers and 1/15 urinary bladder cancers.  FIG. 1D ) Gene symbol: COPS7B, Peptide: NLLEQFILL (SEQ ID NO.: 248); Samples from left to right: 4 cancer cell lines, 6 normal tissues (1 lymph node, 3 spleens, 1 stomach, 1 uterus), 55 cancer tissues (2 brain cancers, 1 breast cancer, 1 cecum cancer, 6 colon cancers, 6 leukocytic leukemia cancers, 2 liver cancers, 10 lung cancers, 8 lymph node cancers, 1 myeloid cell cancer, 3 ovarian cancers, 1 prostate cancer, 1 rectum cancer, 4 skin cancers, 2 stomach cancers, 3 urinary bladder cancers, 4 uterus cancers). Discrepancies regarding the list of tumor types between  FIG. 1D  and Table 4A might be due to the more stringent selection criteria applied in Table 4A (for details please refer to Table 4A). The normal tissue panel and the cancer cell lines and xenografts tested were the same as in  FIG. 1A  to C.  FIG. 1E ) Gene symbol: KDM5B, Peptide: LLSEETPSA (SEQ ID NO.: 2); Samples from left to right: 1 primary culture, 40 cancer tissues (1 bone marrow cancer, 1 brain cancer, 2 breast cancers, 8 head and neck cancers, 4 leukocytic leukemia cancers, 1 liver cancer, 7 lung cancers, 6 lymph node cancers, 2 myeloid cell cancers, 1 ovarian cancer, 3 skin cancers, 3 urinary bladder cancers, 1 uterus cancer).  FIG. 1F ) Gene symbol: CDC42, Peptide: FLLVGTQIDL (SEQ ID NO.: 10); Samples from left to right: 2 cell lines, 10 cancer tissues (2 breast cancers, 1 head and neck cancer, 1 leukocytic leukemia cancer, 1 lung cancer, 4 lymph node cancers, 1 uterus cancer).  FIG. 1G ) Gene symbol: HAPLN3, Peptide: GLLLLVPLL (SEQ ID NO.: 12); Samples from left to right: 16 cancer tissues (1 breast cancer, 1 colon cancer, 1 colorectal cancer, 1 esophageal cancer, 1 gallbladder cancer, 1 head and neck cancer, 2 lung cancers, 5 lymph node cancers, 2 ovarian cancers, 1 skin cancer).  FIG. 1H ) Gene symbol: JAK3, Peptide: HLVPASWKL (SEQ ID NO.: 13); Samples from left to right: 10 cancer tissues (1 leukocytic leukemia cancer, 1 lung cancer, 5 lymph node cancers, 1 ovarian cancer, 1 skin cancer, 1 testis cancer).  FIG. 1I ) Gene symbol: TMEM67, Peptide: FLGSFIDHV (SEQ ID NO.: 26); Samples from left to right: 1 cell line, 9 cancer tissues (1 brain cancer, 1 lung cancer, 1 lymph node cancer, 1 myeloid cell cancer, 2 ovarian cancers, 2 skin cancers, 1 uterus cancer).  FIG. 1J ) Gene symbols: PTTG1, PTTG2, Peptide: ILSTLDVEL (SEQ ID NO.: 30); Samples from left to right: 29 cancer tissues (1 bone marrow cancer, 2 colon cancers, 1 gallbladder cancer, 3 head and neck cancers, 1 kidney cancer, 5 lung cancers, 7 lymph node cancers, 1 ovarian cancer, 5 skin cancers, 2 urinary bladder cancers, 1 uterus cancer).  FIG. 1K ) Gene symbol: DCAKD, Peptide: VILDIPLLFET (SEQ ID NO.: 36); Samples from left to right: 2 cell lines, 20 cancer tissues (1 brain cancer, 1 breast cancer, 1 colorectal cancer, 1 head and neck cancer, 1 leukocytic leukemia cancer, 1 liver cancer, 3 lung cancers, 4 lymph node cancers, 1 myeloid cell cancer, 1 ovarian cancer, 4 skin cancers, 1 uterus cancer).  FIG. 1L ) Gene symbol: KDM2B, Peptide: ALLEGVKNV (SEQ ID NO.: 43); Samples from left to right: 13 cancer tissues (1 breast cancer, 1 leukocytic leukemia cancer, 1 lung cancer, 6 lymph node cancers, 3 ovarian cancers, 1 rectum cancer).  FIG. 1M ) Gene symbol: ACHE, Peptide: SLDLRPLEV (SEQ ID NO.: 74); Samples from left to right: 1 cell line, 2 normal tissues (1 lymph node, 1 spleen), 24 cancer tissues (3 brain cancers, 1 colon cancer, 1 gallbladder cancer, 1 kidney cancer, 1 lung cancer, 12 lymph node cancers, 1 ovarian cancer, 1 skin cancer, 2 stomach cancers, 1 testis cancer).  FIG. 1N ) Gene symbol: CYTB, Peptide: FLYSETWNI (SEQ ID NO.: 254); Samples from left to right: 7 cell lines, 15 cancer tissues (1 colon cancer, 2 head and neck cancers, 3 leukocytic leukemia cancers, 1 liver cancer, 6 lymph node cancers, 1 myeloid cell cancer, 1 skin cancer).  FIG. 1O ) Gene symbol: ACN9, Peptide: FLQEWEVYA (SEQ ID NO.: 257); Samples from left to right: 2 cell lines, 11 cancer tissues (2 leukocytic leukemia cancers, 1 liver cancer, 4 lymph node cancers, 1 myeloid cells cancer, 2 skin cancers, 1 urinary bladder cancer).  FIG. 1P ) Gene symbol: SMC2, Peptide: TVLDGLEFKV (SEQ ID NO.: 259); Samples from left to right: 1 primary culture, 14 cancer tissues (1 head and neck cancer, 3 leukocytic leukemia cancers, 3 lung cancers, 3 lymph node cancers, 1 myeloid cell cancer, 1 ovarian cancer, 2 skin cancers). 
           [0362]      FIGS. 2A to 2C  show exemplary expression profiles of source genes of the present invention that are highly over-expressed or exclusively expressed in NHL in a panel of normal tissues (white bars) and 10 NHL samples (black bars). Tissues from left to right: 6 arteries, 2 blood cell samples, 2 brains, 1 heart, 2 livers, 3 lungs, 2 veins, 1 adipose tissue, 1 adrenal gland, 5 bone marrows, 1 cartilage, 1 colon, 1 esophagus, 2 eyes, 2 gallbladders, 1 kidney, 6 lymph nodes, 4 pancreases, 2 peripheral nerves, 2 pituitary glands, 1 rectum, 2 salivary glands, 2 skeletal muscles, 1 skin, 1 small intestine, 1 spleen, 1 stomach, 1 thyroid gland, 7 tracheas, 1 urinary bladder, 1 breast, 5 ovaries, 5 placentas, 1 prostate, 1 testis, 1 thymus, 1 uterus, 10 NHL samples.  FIG. 2A ) Gene symbol: MIXL1.  FIG. 2B ) Gene symbol: CCR4.  FIG. 2C ) Gene symbol: HIST1H1B. 
           [0363]      FIG. 3  shows exemplary immunogenicity data: flow cytometry results after peptide-specific multimer staining. 
           [0364]      FIGS. 4A to 4C  show exemplary results of peptide-specific in vitro CD8+ T cell responses of a healthy HLA-A*02+ donor. CD8+ T cells were primed using artificial APCs coated with anti-CD28 mAb and HLA-A*02 in complex with Seq ID No 253 peptide (A, left panel), Seq ID No 258 peptide (B, left panel) and Seq ID No 260 peptide (C, left panel), respectively. After three cycles of stimulation, the detection of peptide-reactive cells was performed by 2D multimer staining with A*02/Seq ID No 253 (A), A*02/Seq ID No 258 (B) or A*02/Seq ID No 260 (C). Right panels (A, B and C) show control staining of cells stimulated with irrelevant A*02/peptide complexes. Viable singlet cells were gated for CD8+ lymphocytes. Boolean gates helped excluding false-positive events detected with multimers specific for different peptides. Frequencies of specific multimer+ cells among CD8+ lymphocytes are indicated. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Examples 
     Example 1 
     Identification and Quantitation of Tumor Associated Peptides Presented on the Cell Surface Tissue Samples 
       [0365]    Patients&#39; tumor tissues were obtained from: Asterand (Detroit, Mich., USA &amp; Royston, Herts, UK); ProteoGenex Inc. (Culver City, Calif., USA). 
         [0366]    Normal tissues were obtained from Asterand (Detroit, Mich., USA &amp; Royston, Herts, UK); Bio-Options Inc. (Brea, Calif., USA); BioServe (Beltsville, Md., USA); Capital BioScience Inc. (Rockville, Md., USA); Geneticist Inc. (Glendale, Calif., USA); Kyoto Prefectural University of Medicine (KPUM) (Kyoto, Japan); ProteoGenex Inc. (Culver City, Calif., USA); Tissue Solutions Ltd (Glasgow, UK); University Hospital Geneva (Geneva, Switzerland); University Hospital Heidelberg (Heidelberg, Germany); University Hospital Munich (Munich, Germany); and University Hospital Tübingen (Tübingen, Germany). 
         [0367]    Written informed consents of all patients had been given before surgery or autopsy. Tissues were shock-frozen immediately after excision and stored until isolation of TUMAPs at −70° C. or below. 
         [0000]    Isolation of HLA Peptides from Tissue Samples 
         [0368]    HLA peptide pools from shock-frozen tissue samples were obtained by immune precipitation from solid tissues according to a slightly modified protocol (Falk et al., 1991; Seeger et al., 1999) using the HLA-A*02-specific antibody BB7.2, the HLA-A, -B, C-specific antibody W6/32, CNBr-activated sepharose, acid treatment, and ultrafiltration. 
       Mass Spectrometry Analyses 
       [0369]    The HLA peptide pools as obtained were separated according to their hydrophobicity by reversed-phase chromatography (nanoAcquity UPLC system, Waters) and the eluting peptides were analyzed in LTQ-velos and fusion hybrid mass spectrometers (ThermoElectron) equipped with an ESI source. Peptide pools were loaded directly onto the analytical fused-silica micro-capillary column (75 μm i.d.×250 mm) packed with 1.7 μm C18 reversed-phase material (Waters) applying a flow rate of 400 nL per minute. Subsequently, the peptides were separated using a two-step 180 minute-binary gradient from 10% to 33% B at a flow rate of 300 nL per minute. The gradient was composed of Solvent A (0.1% formic acid in water) and solvent B (0.1% formic acid in acetonitrile). A gold coated glass capillary (PicoTip, New Objective) was used for introduction into the nanoESI source. The LTQ-Orbitrap mass spectrometers were operated in the data-dependent mode using a TOPS strategy. In brief, a scan cycle was initiated with a full scan of high mass accuracy in the Orbitrap (R=30 000), which was followed by MS/MS scans also in the Orbitrap (R=7500) on the 5 most abundant precursor ions with dynamic exclusion of previously selected ions. Tandem mass spectra were interpreted by SEQUEST and additional manual control. The identified peptide sequence was assured by comparison of the generated natural peptide fragmentation pattern with the fragmentation pattern of a synthetic sequence-identical reference peptide. 
         [0370]    Label-free relative LC-MS quantitation was performed by ion counting i.e. by extraction and analysis of LC-MS features (Mueller et al., 2007). The method assumes that the peptide&#39;s LC-MS signal area correlates with its abundance in the sample. Extracted features were further processed by charge state deconvolution and retention time alignment (Mueller et al., 2008; Sturm et al., 2008). Finally, all LC-MS features were cross-referenced with the sequence identification results to combine quantitative data of different samples and tissues to peptide presentation profiles. The quantitative data were normalized in a two-tier fashion according to central tendency to account for variation within technical and biological replicates. Thus, each identified peptide can be associated with quantitative data allowing relative quantification between samples and tissues. In addition, all quantitative data acquired for peptide candidates was inspected manually to assure data consistency and to verify the accuracy of the automated analysis. For each peptide a presentation profile was calculated showing the mean sample presentation as well as replicate variations. The profiles juxtapose NHL samples to a baseline of normal tissue samples. Presentation profiles of exemplary over-presented peptides are shown in  FIGS. 1A-1P . Presentation scores for exemplary peptides are shown in Table 8. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Presentation scores. The table lists peptides 
               
               
                 that are very highly over-presented on tumors 
               
               
                 compared to a panel of normal tissues (+++), 
               
               
                 highly over-presented on tumors compared to a 
               
               
                 panel of normal tissues (++) or over-presented 
               
               
                 on tumors compared to a panel of normal tissues 
               
               
                 (+). The panel of normal tissues considered 
               
               
                 relevant for comparison with tumors consisted of: 
               
               
                 adipose tissue, adrenal gland, artery, vein, 
               
               
                 bone marrow, brain, central and peripheral nerve, 
               
               
                 colon, rectum, small intestine incl. duodenum, 
               
               
                 esophagus, eye, gallbladder, heart, kidney, liver, 
               
               
                 lung, lymph node, mononuclear white blood cells, 
               
               
                 pancreas, parathyroid gland, peritoneum, 
               
               
                 pituitary, pleura, salivary gland, skeletal 
               
               
                 muscle, skin, spleen, stomach, thymus, thyroid 
               
               
                 gland, trachea, ureter, urinary bladder. 
               
             
          
           
               
                 SEQ ID 
                   
                 Peptide 
               
               
                 No. 
                 Sequence 
                 Presentation 
               
               
                   
               
             
          
           
               
                 1 
                 LLSGQLPTI 
                 +++ 
               
               
                   
               
               
                 2 
                 LLSEETPSA 
                 +++ 
               
               
                   
               
               
                 3 
                 LTIDTQYYL 
                 +++ 
               
               
                   
               
               
                 5 
                 VLQGLTFTL 
                 +++ 
               
               
                   
               
               
                 6 
                 TLITLPLLFL 
                 +++ 
               
               
                   
               
               
                 7 
                 NLLGMIFSM 
                 +++ 
               
               
                   
               
               
                 8 
                 ALYAVIEKA 
                 +++ 
               
               
                   
               
               
                 9 
                 FLLDLDPLL 
                 +++ 
               
               
                   
               
               
                 10 
                 FLLVGTQIDL 
                 +++ 
               
               
                   
               
               
                 11 
                 GLDTVVALL 
                 +++ 
               
               
                   
               
               
                 12 
                 GLLLLVPLL 
                 +++ 
               
               
                   
               
               
                 13 
                 HLVPASWKL 
                 +++ 
               
               
                   
               
               
                 15 
                 IIIEDLLEA 
                 +++ 
               
               
                   
               
               
                 16 
                 TLIAAILYL 
                 +++ 
               
               
                   
               
               
                 17 
                 VIIPLLSSV 
                 +++ 
               
               
                   
               
               
                 18 
                 KLTDQPPLV 
                 +++ 
               
               
                   
               
               
                 19 
                 VLEAILPLV 
                 +++ 
               
               
                   
               
               
                 20 
                 YLIAGGDRWL 
                 +++ 
               
               
                   
               
               
                 21 
                 ALFKEAYSL 
                 +++ 
               
               
                   
               
               
                 22 
                 ALKKHLTSV 
                 +++ 
               
               
                   
               
               
                 23 
                 ALVEDIINL 
                 +++ 
               
               
                   
               
               
                 24 
                 AVLGFSFRL 
                 +++ 
               
               
                   
               
               
                 25 
                 FLDTSNQHLL 
                 +++ 
               
               
                   
               
               
                 26 
                 FLGSFIDHV 
                 +++ 
               
               
                   
               
               
                 27 
                 FLNQESFDL 
                 +++ 
               
               
                   
               
               
                 28 
                 FLSNANPSL 
                 +++ 
               
               
                   
               
               
                 29 
                 ILSDVTQGL 
                 +++ 
               
               
                   
               
               
                 30 
                 ILSTLDVEL 
                 +++ 
               
               
                   
               
               
                 31 
                 KLYDEESLL 
                 +++ 
               
               
                   
               
               
                 32 
                 VLNEDELPSV 
                 +++ 
               
               
                   
               
               
                 33 
                 LLANIVPIAMLV 
                 +++ 
               
               
                   
               
               
                 34 
                 LLWEDGVTEA 
                 +++ 
               
               
                   
               
               
                 35 
                 SLSSERYYL 
                 +++ 
               
               
                   
               
               
                 36 
                 VILDIPLLFET 
                 +++ 
               
               
                   
               
               
                 37 
                 VLGNALEGV 
                 +++ 
               
               
                   
               
               
                 38 
                 YLTAEILELAGN 
                 +++ 
               
               
                   
               
               
                 40 
                 FLNSVIVDL 
                 + 
               
               
                   
               
               
                 41 
                 ILASIFETV 
                 +++ 
               
               
                   
               
               
                 43 
                 ALLEGVKNV 
                 + 
               
               
                   
               
               
                 44 
                 FIIEEQSFL 
                 +++ 
               
               
                   
               
               
                 45 
                 FILDDSALYL 
                 + 
               
               
                   
               
               
                 46 
                 FLVEEIFQT 
                 ++ 
               
               
                   
               
               
                 47 
                 GLLPKLTAL 
                 + 
               
               
                   
               
               
                 49 
                 TILGDPQILL 
                 +++ 
               
               
                   
               
               
                 50 
                 LLLDGLIYL 
                 + 
               
               
                   
               
               
                 53 
                 FLREYFERL 
                 +++ 
               
               
                   
               
               
                 54 
                 DIFDAMFSV 
                 +++ 
               
               
                   
               
               
                 55 
                 ILVEVDLVQA 
                 ++ 
               
               
                   
               
               
                 56 
                 GLQDLLFSL 
                 ++ 
               
               
                   
               
               
                 57 
                 LQIGDFVSV 
                 + 
               
               
                   
               
               
                 60 
                 SLLIDVITV 
                 +++ 
               
               
                   
               
               
                 61 
                 SLLNKDLSL 
                 + 
               
               
                   
               
               
                 62 
                 ALAPYLDLL 
                 +++ 
               
               
                   
               
               
                 64 
                 FLVEVSNDV 
                 ++ 
               
               
                   
               
               
                 65 
                 NLTDVSPDL 
                 +++ 
               
               
                   
               
               
                 67 
                 LLATVNVAL 
                 +++ 
               
               
                   
               
               
                 69 
                 TLLAFPLLL 
                 + 
               
               
                   
               
               
                 71 
                 VLLDYVGNVQL 
                 +++ 
               
               
                   
               
               
                 72 
                 TLQEETAVYL 
                 +++ 
               
               
                   
               
               
                 74 
                 SLDLRPLEV 
                 + 
               
               
                   
               
               
                 75 
                 AALKYIPSV 
                 +++ 
               
               
                   
               
               
                 76 
                 ALADLVPVDVVV 
                 +++ 
               
               
                   
               
               
                 77 
                 ALLDVSNNYGI 
                 +++ 
               
               
                   
               
               
                 78 
                 AMEEAVAQV 
                 +++ 
               
               
                   
               
               
                 79 
                 AMKEEKEQL 
                 +++ 
               
               
                   
               
               
                 80 
                 YLFDEIDQA 
                 +++ 
               
               
                   
               
               
                 81 
                 FIFSYITAV 
                 +++ 
               
               
                   
               
               
                 82 
                 FLIDGSSSV 
                 +++ 
               
               
                   
               
               
                 83 
                 FLMDDNMSNTL 
                 +++ 
               
               
                   
               
               
                 84 
                 FLQELQLEHA 
                 +++ 
               
               
                   
               
               
                 85 
                 GLAPAEVVVATVA 
                 +++ 
               
               
                   
               
               
                 86 
                 GLATIRAYL 
                 +++ 
               
               
                   
               
               
                 87 
                 GLFARIIMI 
                 +++ 
               
               
                   
               
               
                 88 
                 GLFDNRSGLPEA 
                 +++ 
               
               
                   
               
               
                 89 
                 GLTALHVAV 
                 +++ 
               
               
                   
               
               
                 90 
                 HLDEVFLEL 
                 +++ 
               
               
                   
               
               
                 91 
                 HLSSTTAQV 
                 +++ 
               
               
                   
               
               
                 92 
                 KLLFEIASA 
                 +++ 
               
               
                   
               
               
                 93 
                 KLLGSLQLL 
                 +++ 
               
               
                   
               
               
                 94 
                 LLAGQATTAYF 
                 +++ 
               
               
                   
               
               
                 95 
                 LLFDLIPVVSV 
                 +++ 
               
               
                   
               
               
                 96 
                 LLLNENESLFL 
                 +++ 
               
               
                   
               
               
                 97 
                 LLNFSPGNL 
                 +++ 
               
               
                   
               
               
                 98 
                 MLQDGIARL 
                 +++ 
               
               
                   
               
               
                 99 
                 QLYDGATALFL 
                 +++ 
               
               
                   
               
               
                 100 
                 RLIRTIAAI 
                 +++ 
               
               
                   
               
               
                 101 
                 SLDQSTWNV 
                 +++ 
               
               
                   
               
               
                 102 
                 SLFAAISGMIL 
                 +++ 
               
               
                   
               
               
                 103 
                 SLQDHLEKV 
                 +++ 
               
               
                   
               
               
                 104 
                 VLLGLPLLV 
                 +++ 
               
               
                   
               
               
                 105 
                 VLTPVILQV 
                 +++ 
               
               
                   
               
               
                 106 
                 VLYELLQYI 
                 +++ 
               
               
                   
               
               
                 107 
                 VQAVSIPEV 
                 +++ 
               
               
                   
               
               
                 108 
                 YLAPENGYLM 
                 +++ 
               
               
                   
               
               
                 109 
                 YLFQFSAAL 
                 +++ 
               
               
                   
               
               
                 110 
                 YQYPFVLGL 
                 +++ 
               
               
                   
               
               
                 111 
                 YLLDTLLSL 
                 +++ 
               
               
                   
               
               
                 112 
                 FLAILPEEV 
                 +++ 
               
               
                   
               
               
                 113 
                 FVIDSFEEL 
                 +++ 
               
               
                   
               
               
                 114 
                 GLSDISPST 
                 +++ 
               
               
                   
               
               
                 115 
                 LLIDIIHFL 
                 +++ 
               
               
                   
               
               
                 116 
                 SLLDNLLTI 
                 + 
               
               
                   
               
               
                 117 
                 VLATILAQL 
                 +++ 
               
               
                   
               
               
                 118 
                 VLDGMIYAI 
                 +++ 
               
               
                   
               
               
                 119 
                 ELCDIILRV 
                 +++ 
               
               
                   
               
               
                 120 
                 VLLGTTWAL 
                 +++ 
               
               
                   
               
               
                 121 
                 YLTGYNFTL 
                 +++ 
               
               
                   
               
               
                 122 
                 AISEAQESV 
                 + 
               
               
                   
               
               
                 123 
                 ALLSAFVQL 
                 ++ 
               
               
                   
               
               
                 124 
                 FLGVVVPTV 
                 +++ 
               
               
                   
               
               
                 125 
                 FVAPPTAAV 
                 +++ 
               
               
                   
               
               
                 126 
                 GLSIFIYRL 
                 +++ 
               
               
                   
               
               
                 128 
                 KLFDASPTFFA 
                 ++ 
               
               
                   
               
               
                 131 
                 VLIEETDQL 
                 +++ 
               
               
                   
               
               
                 132 
                 VLQDQVDEL 
                 +++ 
               
               
                   
               
               
                 133 
                 ALEELTGFREL 
                 +++ 
               
               
                   
               
               
                 134 
                 ALGRLGILSV 
                 +++ 
               
               
                   
               
               
                 135 
                 ALTGLQFQL 
                 +++ 
               
               
                   
               
               
                 136 
                 FIFGIVHLL 
                 +++ 
               
               
                   
               
               
                 137 
                 FIQQERFFL 
                 +++ 
               
               
                   
               
               
                 138 
                 NLINNIFEL 
                 + 
               
               
                   
               
               
                 139 
                 FLASPLVAI 
                 +++ 
               
               
                   
               
               
                 140 
                 FLFEDFVEV 
                 +++ 
               
               
                   
               
               
                 141 
                 FLGELTLQL 
                 +++ 
               
               
                   
               
               
                 142 
                 FLYEDSKSVRL 
                 +++ 
               
               
                   
               
               
                 143 
                 TLHAVDVTL 
                 +++ 
               
               
                   
               
               
                 144 
                 GLITQVDKL 
                 +++ 
               
               
                   
               
               
                 145 
                 GLLHEVVSL 
                 +++ 
               
               
                   
               
               
                 146 
                 GLLQQPPAL 
                 +++ 
               
               
                   
               
               
                 147 
                 GLSEYQRNFL 
                 +++ 
               
               
                   
               
               
                 148 
                 ICAGHVPGV 
                 +++ 
               
               
                   
               
               
                 149 
                 ILNPVTTKL 
                 +++ 
               
               
                   
               
               
                 150 
                 ILSEKEYKL 
                 +++ 
               
               
                   
               
               
                 151 
                 ILVKQSPML 
                 +++ 
               
               
                   
               
               
                 152 
                 KIMYTLVSV 
                 +++ 
               
               
                   
               
               
                 153 
                 KLLKGIYAI 
                 +++ 
               
               
                   
               
               
                 154 
                 KLMNIQQQL 
                 +++ 
               
               
                   
               
               
                 155 
                 KLMTSLVKV 
                 +++ 
               
               
                   
               
               
                 156 
                 KMLEDDLKL 
                 +++ 
               
               
                   
               
               
                 157 
                 KVLEFLAKV 
                 +++ 
               
               
                   
               
               
                 158 
                 KVQDVLHQV 
                 +++ 
               
               
                   
               
               
                 159 
                 LLLSDSGFYL 
                 +++ 
               
               
                   
               
               
                 160 
                 LLPPPSPAA 
                 +++ 
               
               
                   
               
               
                 161 
                 NLMLELETV 
                 +++ 
               
               
                   
               
               
                 162 
                 RLADLKVSI 
                 +++ 
               
               
                   
               
               
                 163 
                 SIFDAVLKGV 
                 +++ 
               
               
                   
               
               
                 164 
                 SLFDGAVISTV 
                 +++ 
               
               
                   
               
               
                 165 
                 KLLEEIEFL 
                 ++ 
               
               
                   
               
               
                 166 
                 SLFSEVASL 
                 +++ 
               
               
                   
               
               
                 167 
                 SLFSITKSV 
                 +++ 
               
               
                   
               
               
                 168 
                 SLLSPLLSV 
                 +++ 
               
               
                   
               
               
                 169 
                 SSLEENLLHQV 
                 +++ 
               
               
                   
               
               
                 170 
                 STIELSENSL 
                 +++ 
               
               
                   
               
               
                 171 
                 TLLDVISAL 
                 +++ 
               
               
                   
               
               
                 172 
                 TLQDSLEFI 
                 +++ 
               
               
                   
               
               
                 173 
                 VILDSVASV 
                 +++ 
               
               
                   
               
               
                 174 
                 VLVEITDVDFAA 
                 +++ 
               
               
                   
               
               
                 175 
                 VMESILLRL 
                 +++ 
               
               
                   
               
               
                 176 
                 YLHIYESQL 
                 +++ 
               
               
                   
               
               
                 177 
                 YLYEAEEATTL 
                 +++ 
               
               
                   
               
               
                 178 
                 YVLQGEFFL 
                 +++ 
               
               
                   
               
               
                 179 
                 FVDTNLYFL 
                 +++ 
               
               
                   
               
               
                 180 
                 GILQLVESV 
                 ++ 
               
               
                   
               
               
                 182 
                 LLPPPPPVA 
                 + 
               
               
                   
               
               
                 183 
                 VLFETVLTI 
                 + 
               
               
                   
               
               
                 185 
                 FIAQLNNVEL 
                 + 
               
               
                   
               
               
                 186 
                 FLDVSRDFV 
                 + 
               
               
                   
               
               
                 188 
                 GLEDEMYEV 
                 ++ 
               
               
                   
               
               
                 189 
                 SLSHLVPAL 
                 + 
               
               
                   
               
               
                 190 
                 GLIELVDQL 
                 ++ 
               
               
                   
               
               
                 191 
                 GLSDISAQV 
                 +++ 
               
               
                   
               
               
                 194 
                 SLAPFDREPFTL 
                 +++ 
               
               
                   
               
               
                 195 
                 ALIPDLNQI 
                 +++ 
               
               
                   
               
               
                 196 
                 TLALAMIYL 
                 ++ 
               
               
                   
               
               
                 200 
                 YLLDFEDRL 
                 + 
               
               
                   
               
               
                 201 
                 YLNISQVNV 
                 ++ 
               
               
                   
               
               
                 203 
                 ILDTIFHKV 
                 +++ 
               
               
                   
               
               
                 204 
                 RLCDIVVNV 
                 +++ 
               
               
                   
               
               
                 207 
                 GLVGLLEQA 
                 ++ 
               
               
                   
               
               
                 211 
                 FIDDLFAFV 
                 +++ 
               
               
                   
               
               
                 212 
                 FLIGQGAHV 
                 + 
               
               
                   
               
               
                 213 
                 YINEDEYEV 
                 + 
               
               
                   
               
               
                 214 
                 FLFDGSMSL 
                 ++ 
               
               
                   
               
               
                 215 
                 QLFEEEIEL 
                 + 
               
               
                   
               
               
                 216 
                 KVVSNLPAI 
                 +++ 
               
               
                   
               
               
                 217 
                 AQFGAVLEV 
                 + 
               
               
                   
               
               
                 218 
                 ALDQFLEGI 
                 + 
               
               
                   
               
               
                 219 
                 ALLELENSV 
                 +++ 
               
               
                   
               
               
                 220 
                 FLAEAPTAL 
                 ++ 
               
               
                   
               
               
                 221 
                 FLAPDNSLLLA 
                 +++ 
               
               
                   
               
               
                 222 
                 FLIETGTLL 
                 + 
               
               
                   
               
               
                 224 
                 FLSPLLPLL 
                 + 
               
               
                   
               
               
                 225 
                 GTYQDVGSLNIGDV 
                 +++ 
               
               
                   
               
               
                 226 
                 GVIDPVPEV 
                 + 
               
               
                   
               
               
                 227 
                 IIAEGIPEA 
                 + 
               
               
                   
               
               
                 231 
                 IVMGAIPSV 
                 + 
               
               
                   
               
               
                 232 
                 KVMEGTVAA 
                 ++ 
               
               
                   
               
               
                 233 
                 MLEVHIPSV 
                 ++ 
               
               
                   
               
               
                 236 
                 SLFDGFFLTA 
                 + 
               
               
                   
               
               
                 237 
                 YLDRLIPQA 
                 ++ 
               
               
                   
               
               
                 239 
                 VLIDDTVLL 
                 ++ 
               
               
                   
               
               
                 242 
                 GILDFZVFL 
                 + 
               
               
                   
               
               
                 243 
                 GLPDLDIYL 
                 +++ 
               
               
                   
               
               
                 244 
                 ILEPFLPAV 
                 + 
               
               
                   
               
               
                 246 
                 KLPVPLESV 
                 + 
               
               
                   
               
               
                 249 
                 VLLESLVEI 
                 +++ 
               
               
                   
               
               
                 252 
                 YLGDLIMAL 
                 + 
               
               
                   
               
               
                 253 
                 YSDDDVPSV 
                 +++ 
               
               
                   
               
               
                 254 
                 FLYSETWNI 
                 +++ 
               
               
                   
               
               
                 255 
                 GMWNPNAPVFL 
                 +++ 
               
               
                   
               
               
                 256 
                 ALQETPPQV 
                 +++ 
               
               
                   
               
               
                 257 
                 FLQEWEVYA 
                 +++ 
               
               
                   
               
               
                 258 
                 RIYPFLLMV 
                 +++ 
               
               
                   
               
               
                 259 
                 TVLDGLEFKV 
                 +++ 
               
               
                   
               
               
                 260 
                 RLDEAFDFV 
                 ++ 
               
               
                   
               
               
                 263 
                 GLMDNEIKV 
                 +++ 
               
               
                   
               
               
                 264 
                 ILTGTPPGV 
                 +++ 
               
               
                   
               
               
                 265 
                 ILWHFVASL 
                 +++ 
               
               
                   
               
               
                 266 
                 QLTEMLPSI 
                 +++ 
               
               
                   
               
               
                 267 
                 SLLETGSDLLL 
                 +++ 
               
               
                   
               
               
                 268 
                 VLFPLPTPL 
                 +++ 
               
               
                   
               
               
                 269 
                 VLQNVAFSV 
                 +++ 
               
               
                   
               
               
                 270 
                 VVVDSDSLAFV 
                 +++ 
               
               
                   
               
               
                 271 
                 YLLDQPVLEQRL 
                 +++ 
               
               
                   
               
               
                 272 
                 KLDHTLSQI 
                 +++ 
               
               
                   
               
               
                 273 
                 AILLPQPPK 
                 +++ 
               
               
                   
               
               
                 274 
                 KLLNLISKL 
                 +++ 
               
               
                   
               
               
                 275 
                 KLMDLEDCAL 
                 +++ 
               
               
                   
               
               
                 276 
                 NMISYVVHL 
                 +++ 
               
               
                   
               
               
                 277 
                 FLIDLNSTHGTFL 
                 + 
               
               
                   
               
               
                 279 
                 NLAGENILNPL 
                 ++ 
               
               
                   
               
               
                 280 
                 SLLNHLPYL 
                 +++ 
               
               
                   
               
               
                 285 
                 SITAVTPLL 
                 + 
               
               
                   
               
               
                 287 
                 ILMGHSLYM 
                 ++ 
               
               
                   
               
               
                 289 
                 SLLAANNLL 
                 +++ 
               
               
                   
               
               
                 290 
                 IASPVIAAV 
                 +++ 
               
               
                   
               
               
                 291 
                 KIIDTAGLSEA 
                 +++ 
               
               
                   
               
               
                 292 
                 KLINSQISL 
                 ++ 
               
               
                   
               
               
                 294 
                 KLYGPEGLELV 
                 + 
               
               
                   
               
               
                 296 
                 FILEPLYKI 
                 ++ 
               
               
                   
               
               
                 298 
                 ALTDVILCV 
                 + 
               
               
                   
               
               
                 299 
                 RLLEEEGVSL 
                 + 
               
               
                   
               
               
                 302 
                 SLAELDEKISA 
                 + 
               
               
                   
               
               
                 303 
                 FVWEASHYL 
                 ++ 
               
               
                   
               
               
                 305 
                 AMLAQQMQL 
                 + 
               
               
                   
               
               
                 307 
                 FLLPVAVKL 
                 ++ 
               
               
                   
               
               
                 308 
                 SLLDQIPEM 
                 + 
               
               
                   
               
             
          
         
       
     
       Example 2 
     Expression Profiling of Genes Encoding the Peptides of the Invention 
       [0371]    Over-presentation or specific presentation of a peptide on tumor cells compared to normal cells is sufficient for its usefulness in immunotherapy, and some peptides are tumor-specific despite their source protein occurring also in normal tissues. Still, mRNA expression profiling adds an additional level of safety in selection of peptide targets for immunotherapies. Especially for therapeutic options with high safety risks, such as affinity-matured TCRs, the ideal target peptide will be derived from a protein that is unique to the tumor and not found on normal tissues. 
       RNA Sources and Preparation 
       [0372]    Surgically removed tissue specimens were provided as indicated above (see Example 1) after written informed consent had been obtained from each patient. Tumor tissue specimens were snap-frozen immediately after surgery and later homogenized with mortar and pestle under liquid nitrogen. Total RNA was prepared from these samples using TRI Reagent (Ambion, Darmstadt, Germany) followed by a cleanup with RNeasy (QIAGEN, Hilden, Germany); both methods were performed according to the manufacturer&#39;s protocol. 
         [0373]    Total RNA from healthy human tissues for RNASeq experiments was obtained from: Asterand (Detroit, Mich., USA &amp; Royston, Herts, UK); BioCat GmbH (Heidelberg, Germany); BioServe (Beltsville, Md., USA); Capital BioScience Inc. (Rockville, Md., USA); Geneticist Inc. (Glendale, Calif., USA); Istituto Nazionale Tumori “Pascale” (Naples, Italy); ProteoGenex Inc. (Culver City, Calif., USA); University Hospital Heidelberg (Heidelberg, Germany). Total RNA from tumor tissues for RNASeq experiments was obtained from: Asterand (Detroit, Mich., USA &amp; Royston, Herts, UK); ProteoGenex Inc. (Culver City, Calif., USA). 
         [0374]    Quality and quantity of all RNA samples were assessed on an Agilent 2100 Bioanalyzer (Agilent, Waldbronn, Germany) using the RNA 6000 Pico LabChip Kit (Agilent). 
       RNAseq Experiments 
       [0375]    Gene expression analysis of—tumor and normal tissue RNA samples was performed by next generation sequencing (RNAseq) by CeGaT (Tübingen, Germany). Briefly, sequencing libraries are prepared using the Illumina HiSeq v4 reagent kit according to the provider&#39;s protocol (Illumina Inc., San Diego, Calif., USA), which includes RNA fragmentation, cDNA conversion and addition of sequencing adaptors. Libraries derived from multiple samples are mixed equimolar and sequenced on the Illumina HiSeq 2500 sequencer according to the manufacturer&#39;s instructions, generating 50 bp single end reads. Processed reads are mapped to the human genome (GRCh38) using the STAR software. Expression data are provided on transcript level as RPKM (Reads Per Kilobase per Million mapped reads, generated by the software Cufflinks) and on exon level (total reads, generated by the software Bedtools), based on annotations of the ensembl sequence database (Ensembl77). Exon reads are normalized for exon length and alignment size to obtain RPKM values. Exemplary expression profiles of source genes of the present invention that are highly over-expressed or exclusively expressed in NHL are shown in  FIGS. 2A-2C . Expression scores for further exemplary genes are shown in Table 9. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 Expression scores. The table lists peptides from 
               
               
                 genes that are very highly over-expressed in 
               
               
                 tumors compared to a panel of normal tissues 
               
               
                 (+++), highly over-expressed in tumors compared 
               
               
                 to a panel of normal tissues (++) or over- 
               
               
                 expressed in tumors compared to a panel of 
               
               
                 normal tissues (+). The baseline for this score 
               
               
                 was calculated from measurements of the following 
               
               
                 relevant normal tissues: adipose tissue, adrenal 
               
               
                 gland, artery, blood cells, bone marrow, brain, 
               
               
                 cartilage, colon, esophagus, eye, gallbladder, 
               
               
                 heart, kidney, liver, lung, lymph node, pancreas,  
               
               
                 pituitary, rectum, salivary gland, skeletal 
               
               
                 muscle, skin, small intestine, spleen, stomach, 
               
               
                 thyroid gland, trachea, urinary bladder, and 
               
               
                 vein. In case expression data for several samples 
               
               
                 of the same tissue type were available, the 
               
               
                 arithmetic mean of all respective samples was 
               
               
                 used for the calculation. 
               
             
          
           
               
                   
                   
                 Gene 
               
               
                 SEQ ID No 
                 Sequence 
                 Expression 
               
               
                   
               
               
                   9 
                 FLLDLDPLL 
                 ++ 
               
               
                   
               
               
                  21 
                 ALFKEAYSL 
                 + 
               
               
                   
               
               
                  25 
                 FLDTSNQHLL 
                 ++ 
               
               
                   
               
               
                  30 
                 ILSTLDVEL 
                 ++ 
               
               
                   
               
               
                  38 
                 YLTAEILELAGN 
                 ++ 
               
               
                   
               
               
                  43 
                 ALLEGVKNV 
                 + 
               
               
                   
               
               
                  55 
                 ILVEVDLVQA 
                 + 
               
               
                   
               
               
                  56 
                 GLQDLLFSL 
                 + 
               
               
                   
               
               
                  61 
                 SLLNKDLSL 
                 + 
               
               
                   
               
               
                  91 
                 HLSSTTAQV 
                 ++ 
               
               
                   
               
               
                 102 
                 SLFAAISGMIL 
                 +++ 
               
               
                   
               
               
                 106 
                 VLYELLQYI 
                 +++ 
               
               
                   
               
               
                 112 
                 FLAILPEEV 
                 ++ 
               
               
                   
               
               
                 113 
                 FVIDSFEEL 
                 +++ 
               
               
                   
               
               
                 116 
                 SLLDNLLTI 
                 + 
               
               
                   
               
               
                 133 
                 ALEELTGFREL 
                 + 
               
               
                   
               
               
                 135 
                 ALTGLQFQL 
                 +++ 
               
               
                   
               
               
                 142 
                 FLYEDSKSVRL 
                 +++ 
               
               
                   
               
               
                 143 
                 TLHAVDVTL 
                 +++ 
               
               
                   
               
               
                 146 
                 GLLQQPPAL 
                 + 
               
               
                   
               
               
                 148 
                 ICAGHVPGV 
                 +++ 
               
               
                   
               
               
                 155 
                 KLMTSLVKV 
                 +++ 
               
               
                   
               
               
                 157 
                 KVLEFLAKV 
                 +++ 
               
               
                   
               
               
                 158 
                 KVQDVLHQV 
                 +++ 
               
               
                   
               
               
                 159 
                 LLLSDSGFYL 
                 ++ 
               
               
                   
               
               
                 160 
                 LLPPPSPAA 
                 +++ 
               
               
                   
               
               
                 161 
                 NLMLELETV 
                 +++ 
               
               
                   
               
               
                 162 
                 RLADLKVSI 
                 +++ 
               
               
                   
               
               
                 167 
                 SLFSITKSV 
                 +++ 
               
               
                   
               
               
                 170 
                 STIELSENSL 
                 ++ 
               
               
                   
               
               
                 174 
                 VLVEITDVDFAA 
                 + 
               
               
                   
               
               
                 175 
                 VMESILLRL 
                 +++ 
               
               
                   
               
               
                 178 
                 YVLQGEFFL 
                 +++ 
               
               
                   
               
               
                 183 
                 VLFETVLTI 
                 + 
               
               
                   
               
               
                 192 
                 GMAAEVPKV 
                 + 
               
               
                   
               
               
                 199 
                 SLNSTTWKV 
                 +++ 
               
               
                   
               
               
                 202 
                 ALAAGGYDV 
                 +++ 
               
               
                   
               
               
                 222 
                 FLIETGTLL 
                 ++ 
               
               
                   
               
               
                 225 
                 GTYQDVGSLNIGDV 
                 ++ 
               
               
                   
               
               
                 229 
                 ILSPWGAEV 
                 ++ 
               
               
                   
               
               
                 238 
                 YQYGAVVTL 
                 ++ 
               
               
                   
               
               
                 256 
                 ALQETPPQV 
                 + 
               
               
                   
               
               
                 260 
                 RLDEAFDFV 
                 ++ 
               
               
                   
               
               
                 268 
                 VLFPLPTPL 
                 + 
               
               
                   
               
               
                 276 
                 NMISYVVHL 
                 +++ 
               
               
                   
               
               
                 294 
                 KLYGPEGLELV 
                 +++ 
               
               
                   
               
               
                 297 
                 ILQNGLETL 
                 +++ 
               
               
                   
               
               
                 298 
                 ALTDVILCV 
                 +++ 
               
               
                   
               
             
          
         
       
     
       Example 3 
     In Vitro Immunogenicity for MHC Class I Presented Peptides 
       [0376]    In order to obtain information regarding the immunogenicity of the TUMAPs of the present invention, the inventors performed investigations using an in vitro T-cell priming assay based on repeated stimulations of CD8+ T cells with artificial antigen presenting cells (aAPCs) loaded with peptide/MHC complexes and anti-CD28 antibody. This way the inventors could show immunogenicity for HLA-A*0201 restricted TUMAPs of the invention, demonstrating that these peptides are T-cell epitopes against which CD8+ precursor T cells exist in humans (Table 10A). 
       In Vitro Priming of CD8+ T Cells 
       [0377]    In order to perform in vitro stimulations by artificial antigen presenting cells loaded with peptide-MHC complex (pMHC) and anti-CD28 antibody, the inventors first isolated CD8+ T cells from fresh HLA-A*02 leukapheresis products via positive selection using CD8 microbeads (Miltenyi Biotec, Bergisch-Gladbach, Germany) of healthy donors obtained from the University clinics Mannheim, Germany, after informed consent. 
         [0378]    PBMCs and isolated CD8+ lymphocytes were incubated in T-cell medium (TCM) until use consisting of RPMI-Glutamax (Invitrogen, Karlsruhe, Germany) supplemented with 10% heat inactivated human AB serum (PAN-Biotech, Aidenbach, Germany), 100 U/ml Penicillin/100 μg/ml Streptomycin (Cambrex, Cologne, Germany), 1 mM sodium pyruvate (CC Pro, Oberdorla, Germany), 20 μg/ml Gentamycin (Cambrex). 2.5 ng/ml IL-7 (PromoCell, Heidelberg, Germany) and 10 U/ml IL-2 (Novartis Pharma, Nürnberg, Germany) were also added to the TCM at this step. 
         [0379]    Generation of pMHC/anti-CD28 coated beads, T-cell stimulations and readout was performed in a highly defined in vitro system using four different pMHC molecules per stimulation condition and 8 different pMHC molecules per readout condition. 
         [0380]    The purified co-stimulatory mouse IgG2a anti human CD28 Ab 9.3 (Jung et al., 1987) was chemically biotinylated using Sulfo-N-hydroxysuccinimidobiotin as recommended by the manufacturer (Perbio, Bonn, Germany). Beads used were 5.6 μm diameter streptavidin coated polystyrene particles (Bangs Laboratories, Illinois, USA). 
         [0381]    pMHC used for positive and negative control stimulations were A*0201/MLA-001 (peptide ELAGIGILTV (SEQ ID NO. 329) from modified Melan-A/MART-1) and A*0201/DDX5-001 (YLLPAIVHI from DDX5, SEQ ID NO. 330), respectively. 
         [0382]    800.000 beads/200 μl were coated in 96-well plates in the presence of 4×12.5 ng different biotin-pMHC, washed and 600 ng biotin anti-CD28 were added subsequently in a volume of 200 μl. Stimulations were initiated in 96-well plates by co-incubating 1×10 6  CD8+ T cells with 2×10 5  washed coated beads in 200 μl TCM supplemented with 5 ng/ml IL-12 (PromoCell) for 3 days at 37° C. Half of the medium was then exchanged by fresh TCM supplemented with 80 U/ml IL-2 and incubating was continued for 4 days at 37° C. This stimulation cycle was performed for a total of three times. For the pMHC multimer readout using 8 different pMHC molecules per condition, a two-dimensional combinatorial coding approach was used as previously described (Andersen et al., 2012) with minor modifications encompassing coupling to 5 different fluorochromes. Finally, multimeric analyses were performed by staining the cells with Live/dead near IR dye (Invitrogen, Karlsruhe, Germany), CD8-FITC antibody clone SK1 (BD, Heidelberg, Germany) and fluorescent pMHC multimers. For analysis, a BD LSRII SORP cytometer equipped with appropriate lasers and filters was used. Peptide specific cells were calculated as percentage of total CD8+ cells. Evaluation of multimeric analysis was done using the FlowJo software (Tree Star, Oreg., USA). In vitro priming of specific multimer+CD8+ lymphocytes was detected by comparing to negative control stimulations. Immunogenicity for a given antigen was detected if at least one evaluable in vitro stimulated well of one healthy donor was found to contain a specific CD8+ T-cell line after in vitro stimulation (i.e. this well contained at least 1% of specific multimer+ among CD8+ T-cells and the percentage of specific multimer+ cells was at least 10× the median of the negative control stimulations). 
       In Vitro Immunogenicity for NHL Peptides 
       [0383]    For tested HLA class I peptides, in vitro immunogenicity could be demonstrated by generation of peptide specific T-cell lines. Exemplary flow cytometry results after TUMAP-specific multimer staining for 2 peptides of the invention are shown in  FIG. 3  together with corresponding negative controls. Results for ten peptides from the invention are summarized in Tables 10A and 10B. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 10A 
               
             
             
               
                   
               
               
                 in vitro immunogenicity of HLA class I peptides 
               
               
                 of the invention  
               
               
                 Exemplary results of in vitro immunogenicity 
               
               
                 experiments conducted by the applicant for the 
               
               
                  peptides of the invention. &lt;20% = +; 20%-49% = 
               
               
                 ++; 50 -69% = +++; &gt; = 70% = ++++ 
               
             
          
           
               
                 Seq ID 
                 Sequence 
                 wells 
               
               
                   
               
               
                 319 
                 SLYKGLLSV 
                 ++ 
               
               
                   
               
               
                 320 
                 LLWGNLPEI 
                 ++ 
               
               
                   
               
               
                 321 
                 KLLAVIHEL 
                 ++ 
               
               
                   
               
               
                 322 
                 TLTNIIHNL 
                 ++  
               
               
                   
               
               
                 323 
                 ILVDWLVQV 
                 ++ 
               
               
                   
               
               
                 324 
                 LLYDAVHIV 
                 ++ 
               
               
                   
               
               
                 325 
                 FLFVDPELV 
                 +++ 
               
               
                   
               
               
                 326 
                 KLTDVGIATL 
                 ++++ 
               
               
                   
               
               
                 327 
                 MLFGHPLLVSV 
                 ++ 
               
               
                   
               
               
                 328 
                 ILFPDIIARA 
                 ++++ 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 10B 
               
             
             
               
                   
               
               
                 In vitro immunogenicity of HLA class I peptides  
               
               
                 of the invention 
               
               
                 Exemplary results of in vitro immunogenicity 
               
               
                 experiments conducted by the applicant for 
               
               
                 HLA-A*02 restricted peptides of the invention. 
               
               
                 Results of in vitro immunogenicity 
               
               
                 experiments are indicated. Percentage of positive 
               
               
                 wells and donors (among evaluable) are 
               
               
                 summarized as indicated &lt;20% = +; 20%-49% = 
               
               
                 ++; 50%-69 = +++; &gt; =70% = ++++ 
               
             
          
           
               
                 SEQ ID NO: 
                 Sequence 
                 Wells positive [%] 
               
               
                   
               
               
                   1 
                 LLSGQLPTI 
                 ″+++″ 
               
               
                   
               
               
                   2 
                 LLSEETPSA 
                 ″+″ 
               
               
                   
               
               
                   3 
                 LTIDTQYYL 
                 ″+″ 
               
               
                   
               
               
                   5 
                 VLQGLTFTL 
                 ″+++″ 
               
               
                   
               
               
                   7 
                 NLLGMIFSM 
                 ″++++″ 
               
               
                   
               
               
                   8 
                 ALYAVIEKA 
                 ″+″ 
               
               
                   
               
               
                   9 
                 FLLDLDPLL 
                 ″++″ 
               
               
                   
               
               
                  12 
                 GLLLLVPLL 
                 ″+++″ 
               
               
                   
               
               
                  13 
                 HLVPASWKL 
                 ″+++″ 
               
               
                   
               
               
                  17 
                 VIIPLLSSV 
                 ″++″ 
               
               
                   
               
               
                  19 
                 VLEAILPLV 
                 ″+″ 
               
               
                   
               
               
                  21 
                 ALFKEAYSL 
                 ″+″ 
               
               
                   
               
               
                  22 
                 ALKKHLTSV 
                 ″++++″ 
               
               
                   
               
               
                  24 
                 AVLGFSFRL 
                 ″++++″ 
               
               
                   
               
               
                  25 
                 FLDTSNQHLL 
                 ″+″ 
               
               
                   
               
               
                  26 
                 FLGSFIDHV 
                 ″+″ 
               
               
                   
               
               
                  27 
                 FLNQESFDL 
                 ″+″ 
               
               
                   
               
               
                  28 
                 FLSNANPSL 
                 ″++++″ 
               
               
                   
               
               
                  29 
                 ILSDVTQGL 
                 ″+″ 
               
               
                   
               
               
                  30 
                 ILSTLDVEL 
                 ″++″ 
               
               
                   
               
               
                  33 
                 LLANIVPIAMLV 
                 ″+″ 
               
               
                   
               
               
                  35 
                 SLSSERYYL 
                 ″++++″ 
               
               
                   
               
               
                  36 
                 VILDIPLLFET 
                 ″++″ 
               
               
                   
               
               
                  37 
                 VLGNALEGV 
                 ″+″ 
               
               
                   
               
               
                  40 
                 FLNSVIVDL 
                 ″+++″ 
               
               
                   
               
               
                  41 
                 ILASIFETV 
                 ″+++″ 
               
               
                   
               
               
                  42 
                 YLQDLVERA 
                 ″+++″ 
               
               
                   
               
               
                  43 
                 ALLEGVKNV 
                 ″++″ 
               
               
                   
               
               
                  44 
                 FIIEEQSFL 
                 ″+″ 
               
               
                   
               
               
                  46 
                 FLVEEIFQT 
                 ″+″ 
               
               
                   
               
               
                  47 
                 GLLPKLTAL 
                 ″++″ 
               
               
                   
               
               
                  51 
                 SLLGNSPVL 
                 ″+++″ 
               
               
                   
               
               
                  52 
                 VLLEDVDAAFL 
                 ″+″ 
               
               
                   
               
               
                  53 
                 FLREYFERL 
                 ″+++″ 
               
               
                   
               
               
                  57 
                 LQIGDFVSV 
                 ″++++″ 
               
               
                   
               
               
                  59 
                 RLHREVAQV 
                 ″+″ 
               
               
                   
               
               
                  60 
                 SLLIDVITV 
                 ″+++″ 
               
               
                   
               
               
                  61 
                 SLLNKDLSL 
                 ″+″ 
               
               
                   
               
               
                  62 
                 ALAPYLDLL 
                 ″++″ 
               
               
                   
               
               
                  66 
                 KLAPIPVEL 
                 ″++″ 
               
               
                   
               
               
                  67 
                 LLATVNVAL 
                 ″+″ 
               
               
                   
               
               
                  68 
                 QIAAFLFTV 
                 ″+++″ 
               
               
                   
               
               
                  73 
                 YLGEEYPEV 
                 ″+″ 
               
               
                   
               
               
                  74 
                 SLDLRPLEV 
                 ″++″ 
               
               
                   
               
               
                 253 
                 YSDDDVPSV 
                 ″+++″ 
               
               
                   
               
               
                 254 
                 FLYSETWNI 
                 ″+″ 
               
               
                   
               
               
                 256 
                 ALQETPPQV 
                 ″+″ 
               
               
                   
               
               
                 258 
                 RIYPFLLMV 
                 ″++++″ 
               
               
                   
               
               
                 260 
                 RLDEAFDFV 
                 ″++++″ 
               
               
                   
               
               
                 261 
                 FLPETRIMTSV 
                 ″+″ 
               
               
                   
               
               
                 262 
                 LMGPVVHEV 
                 ″++″ 
               
               
                   
               
             
          
         
       
     
       Example 4 
     Synthesis of Peptides 
       [0384]    All peptides were synthesized using standard and well-established solid phase peptide synthesis using the Fmoc-strategy. Identity and purity of each individual peptide have been determined by mass spectrometry and analytical RP-HPLC. The peptides were obtained as white to off-white lyophilizates (trifluoro acetate salt) in purities of &gt;50%. All TUMAPs are preferably administered as trifluoro-acetate salts or acetate salts, other salt-forms are also possible. 
       Example 5 
     MHC Binding Assays 
       [0385]    Candidate peptides for T cell based therapies according to the present invention were further tested for their MHC binding capacity (affinity). The individual peptide-MHC complexes were produced by UV-ligand exchange, where a UV-sensitive peptide is cleaved upon UV-irradiation, and exchanged with the peptide of interest as analyzed. Only peptide candidates that can effectively bind and stabilize the peptide-receptive MHC molecules prevent dissociation of the MHC complexes. To determine the yield of the exchange reaction, an ELISA was performed based on the detection of the light chain (β2m) of stabilized MHC complexes. The assay was performed as generally described in Rodenko et al. (Rodenko et al., 2006). 
         [0386]    96 well MAXISorp plates (NUNC) were coated over night with 2 ug/ml streptavidin in PBS at room temperature, washed 4× and blocked for 1 h at 37° C. in 2% BSA containing blocking buffer. Refolded HLA-A*02:01/MLA-001 monomers served as standards, covering the range of 15-500 ng/ml. Peptide-MHC monomers of the UV-exchange reaction were diluted 100 fold in blocking buffer. Samples were incubated for 1 h at 37° C., washed four times, incubated with 2 ug/ml HRP conjugated anti-β2m for 1 h at 37° C., washed again and detected with TMB solution that is stopped with NH2SO4. Absorption was measured at 450 nm. Candidate peptides that show a high exchange yield (preferably higher than 50%, most preferred higher than 75%) are generally preferred for a generation and production of antibodies or fragments thereof, and/or T cell receptors or fragments thereof, as they show sufficient avidity to the MHC molecules and prevent dissociation of the MHC complexes. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 MHC class I binding scores. 
               
               
                 Binding of HLA-class I restricted peptides to 
               
               
                 HLA-A*02:01 was ranged by peptide exchange 
               
               
                 yield: ≧10% = +; ≧20% = ++; ≧50 = +++; 
               
               
                 ≧75% = ++++ 
               
             
          
           
               
                 SEQ ID NO: 
                 Sequence 
                 Peptide exchange 
               
               
                   
               
               
                   1 
                 LLSGQLPTI 
                 ″+++″ 
               
               
                   
               
               
                   2 
                 LLSEETPSA 
                 ″+++″ 
               
               
                   
               
               
                   3 
                 LTIDTQYYL 
                 ″+++″ 
               
               
                   
               
               
                   4 
                 TLLGFFLAKV 
                 ″++″ 
               
               
                   
               
               
                   5 
                 VLQGLTFTL 
                 ″+++″ 
               
               
                   
               
               
                   6 
                 TLITLPLLFL 
                 ″+++″ 
               
               
                   
               
               
                   7 
                 NLLGMIFSM 
                 ″++++″ 
               
               
                   
               
               
                   8 
                 ALYAVIEKA 
                 ″+++″ 
               
               
                   
               
               
                   9 
                 FLLDLDPLL 
                 ″+++″ 
               
               
                   
               
               
                  10 
                 FLLVGTQIDL 
                 ″+++″ 
               
               
                   
               
               
                  11 
                 GLDTVVALL 
                 ″+++″ 
               
               
                   
               
               
                  12 
                 GLLLLVPLL 
                 ″+++″ 
               
               
                   
               
               
                  13 
                 HLVPASWKL 
                 ″+++″ 
               
               
                   
               
               
                  14 
                 LLSDPTPGA 
                 ″++″ 
               
               
                   
               
               
                  15 
                 IIIEDLLEA 
                 ″++++″ 
               
               
                   
               
               
                  16 
                 TLIAAILYL 
                 ″++″ 
               
               
                   
               
               
                  17 
                 VIIPLLSSV 
                 ″+++″ 
               
               
                   
               
               
                  18 
                 KLTDQPPLV 
                 ″+++″ 
               
               
                   
               
               
                  19 
                 VLEAILPLV 
                 ″++++″ 
               
               
                   
               
               
                  21 
                 ALFKEAYSL 
                 ″+++″ 
               
               
                   
               
               
                  22 
                 ALKKHLTSV 
                 ″+++″ 
               
               
                   
               
               
                  23 
                 ALVEDIINL 
                 ″++++″ 
               
               
                   
               
               
                  24 
                 AVLGFSFRL 
                 ″+++″ 
               
               
                   
               
               
                  25 
                 FLDTSNQHLL 
                 ″+++″ 
               
               
                   
               
               
                  26 
                 FLGSFIDHV 
                 ″+++″ 
               
               
                   
               
               
                  27 
                 FLNQESFDL 
                 ″+++″ 
               
               
                   
               
               
                  28 
                 FLSNANPSL 
                 ″+++″ 
               
               
                   
               
               
                  29 
                 ILSDVTQGL 
                 ″+++″ 
               
               
                   
               
               
                  30 
                 ILSTLDVEL 
                 ″+++″ 
               
               
                   
               
               
                  31 
                 KLYDEESLL 
                 ″++++″ 
               
               
                   
               
               
                  32 
                 VLNEDELPSV 
                 ″+++″ 
               
               
                   
               
               
                  33 
                 LLANIVPIAMLV 
                 ″++++″ 
               
               
                   
               
               
                  34 
                 LLWEDGVTEA 
                 ″+++″ 
               
               
                   
               
               
                  35 
                 SLSSERYYL 
                 ″+++″ 
               
               
                   
               
               
                  36 
                 VILDIPLLFET 
                 ″+++″ 
               
               
                   
               
               
                  37 
                 VLGNALEGV 
                 ″+++″ 
               
               
                   
               
               
                  38 
                 YLTAEILELAGN 
                 ″++″ 
               
               
                   
               
               
                  39 
                 QLLPQGIVPAL 
                 ″+++″ 
               
               
                   
               
               
                  40 
                 FLNSVIVDL 
                 ″++++″ 
               
               
                   
               
               
                  41 
                 ILASIFETV 
                 ″++++″ 
               
               
                   
               
               
                  42 
                 YLQDLVERA 
                 ″++++″ 
               
               
                   
               
               
                  43 
                 ALLEGVKNV 
                 ″+++″ 
               
               
                   
               
               
                  44 
                 FIIEEQSFL 
                 ″+++″ 
               
               
                   
               
               
                  45 
                 FILDDSALYL 
                 ″+++″ 
               
               
                   
               
               
                  46 
                 FLVEEIFQT 
                 ″+++″ 
               
               
                   
               
               
                  47 
                 GLLPKLTAL 
                 ″+++″ 
               
               
                   
               
               
                  48 
                 KILDEDLYI 
                 ″+++″ 
               
               
                   
               
               
                  49 
                 TILGDPQILL 
                 ″++++″ 
               
               
                   
               
               
                  50 
                 LLLDGLIYL 
                 ″+++″ 
               
               
                   
               
               
                  51 
                 SLLGNSPVL 
                 ″++++″ 
               
               
                   
               
               
                  52 
                 VLLEDVDAAFL 
                 ″++++″ 
               
               
                   
               
               
                  53 
                 FLREYFERL 
                 ″++++″ 
               
               
                   
               
               
                  54 
                 DIFDAMFSV 
                 ″+++++″ 
               
               
                   
               
               
                  55 
                 ILVEVDLVQA 
                 ″++++″ 
               
               
                   
               
               
                  56 
                 GLQDLLFSL 
                 ″+++″ 
               
               
                   
               
               
                  57 
                 LQIGDFVSV 
                 ″++++″ 
               
               
                   
               
               
                  58 
                 QLAPFLPQL 
                 ″+++″ 
               
               
                   
               
               
                  59 
                 RLHREVAQV 
                 ″+++″ 
               
               
                   
               
               
                  60 
                 SLLIDVITV 
                 ″+++″ 
               
               
                   
               
               
                  61 
                 SLLNKDLSL 
                 ″++++″ 
               
               
                   
               
               
                  62 
                 ALAPYLDLL 
                 ″++++″ 
               
               
                   
               
               
                  63 
                 ALIEEAYGL 
                 ″+++″ 
               
               
                   
               
               
                  64 
                 FLVEVSNDV 
                 ″++++″ 
               
               
                   
               
               
                  65 
                 NLTDVSPDL 
                 ″+++″ 
               
               
                   
               
               
                  66 
                 KLAPIPVEL 
                 ″++++″ 
               
               
                   
               
               
                  67 
                 LLATVNVAL 
                 ″++++″ 
               
               
                   
               
               
                  68 
                 QIAAFLFTV 
                 ″++++″ 
               
               
                   
               
               
                  69 
                 TLLAFPLLL 
                 ″++++″ 
               
               
                   
               
               
                  70 
                 VLIEILQKA 
                 ″++++″ 
               
               
                   
               
               
                  71 
                 VLLDYVGNVQL 
                 ″++++″ 
               
               
                   
               
               
                  72 
                 TLQEETAVYL 
                 ″++″ 
               
               
                   
               
               
                  73 
                 YLGEEYPEV 
                 ″+++″ 
               
               
                   
               
               
                  74 
                 SLDLRPLEV 
                 ″++++″ 
               
               
                   
               
               
                  75 
                 AALKYIPSV 
                 ″+++″ 
               
               
                   
               
               
                  76 
                 ALADLVPVDVVV 
                 ″++++″ 
               
               
                   
               
               
                  77 
                 ALLDVSNNYGI 
                 ″++++″ 
               
               
                   
               
               
                  78 
                 AMEEAVAQV 
                 ″+++″ 
               
               
                   
               
               
                  79 
                 AMKEEKEQL 
                 ″++″ 
               
               
                   
               
               
                  80 
                 YLFDEIDQA 
                 ″+++″ 
               
               
                   
               
               
                  81 
                 FIFSYITAV 
                 ″++″ 
               
               
                   
               
               
                  82 
                 FLIDGSSSV 
                 ″+++″ 
               
               
                   
               
               
                  83 
                 FLMDDNMSNTL 
                 ″+++″ 
               
               
                   
               
               
                  84 
                 FLQELQLEHA 
                 ″+++″ 
               
               
                   
               
               
                  85 
                 GLAPAEVVVATVA 
                 ″+++″ 
               
               
                   
               
               
                  86 
                 GLATIRAYL 
                 ″+++″ 
               
               
                   
               
               
                  87 
                 GLFARIIMI 
                 ″++″ 
               
               
                   
               
               
                  88 
                 GLFDNRSGLPEA 
                 ″+++″ 
               
               
                   
               
               
                  89 
                 GLTALHVAV 
                 ″+++″ 
               
               
                   
               
               
                  90 
                 HLDEVFLEL 
                 ″+++″ 
               
               
                   
               
               
                  91 
                 HLSSTTAQV 
                 ″++″ 
               
               
                   
               
               
                  92 
                 KLLFEIASA 
                 ″+++″ 
               
               
                   
               
               
                  93 
                 KLLGSLQLL 
                 ″++++″ 
               
               
                   
               
               
                  94 
                 LLAGQATTAYF 
                 ″+++″ 
               
               
                   
               
               
                  95 
                 LLFDLIPVVSV 
                 ″+++″ 
               
               
                   
               
               
                  96 
                 LLLNENESLFL 
                 ″+++″ 
               
               
                   
               
               
                  97 
                 LLNFSPGNL 
                 ″+″ 
               
               
                   
               
               
                  98 
                 MLQDGIARL 
                 ″+++″ 
               
               
                   
               
               
                  99 
                 QLYDGATALFL 
                 ″++″ 
               
               
                   
               
               
                 100 
                 RLIRTIAAI 
                 ″+++″ 
               
               
                   
               
               
                 101 
                 SLDQSTWNV 
                 ″++++″ 
               
               
                   
               
               
                 102 
                 SLFAAISGMIL 
                 ″+++″ 
               
               
                   
               
               
                 103 
                 SLQDHLEKV 
                 ″+++″ 
               
               
                   
               
               
                 104 
                 VLLGLPLLV 
                 ″+++″ 
               
               
                   
               
               
                 105 
                 VLTPVILQV 
                 ″+++″ 
               
               
                   
               
               
                 106 
                 VLYELLQYI 
                 ″++++″ 
               
               
                   
               
               
                 107 
                 VQAVSIPEV 
                 ″+++″ 
               
               
                   
               
               
                 108 
                 YLAPENGYLM 
                 ″+++″ 
               
               
                   
               
               
                 109 
                 YLFQFSAAL 
                 ″+++″ 
               
               
                   
               
               
                 110 
                 YQYPFVLGL 
                 ″++++″ 
               
               
                   
               
               
                 111 
                 YLLDTLLSL 
                 ″+++″ 
               
               
                   
               
               
                 112 
                 FLAILPEEV 
                 ″+++″ 
               
               
                   
               
               
                 113 
                 FVIDSFEEL 
                 ″+++″ 
               
               
                   
               
               
                 114 
                 GLSDISPST 
                 ″++″ 
               
               
                   
               
               
                 115 
                 LLIDIIHFL 
                 ″++++″ 
               
               
                   
               
               
                 116 
                 SLLDNLLTI 
                 ″+++″ 
               
               
                   
               
               
                 117 
                 VLATILAQL 
                 ″++++″ 
               
               
                   
               
               
                 118 
                 VLDGMIYAI 
                 ″+++″ 
               
               
                   
               
               
                 119 
                 ELCDIILRV 
                 ″+++″ 
               
               
                   
               
               
                 120 
                 VLLGTTWAL 
                 ″+++″ 
               
               
                   
               
               
                 121 
                 YLTGYNFTL 
                 ″+++″ 
               
               
                   
               
               
                 122 
                 AISEAQESV 
                 ″++″ 
               
               
                   
               
               
                 123 
                 ALLSAFVQL 
                 ″+++″ 
               
               
                   
               
               
                 124 
                 FLGVVVPTV 
                 ″+++″ 
               
               
                   
               
               
                 125 
                 FVAPPTAAV 
                 ″+++″ 
               
               
                   
               
               
                 127 
                 HLMEENMIVYV 
                 ″+++″ 
               
               
                   
               
               
                 128 
                 KLFDASPTFFA 
                 ″+++″ 
               
               
                   
               
               
                 129 
                 SLFEASQQL 
                 ″+++″ 
               
               
                   
               
               
                 130 
                 VIFSYVLGV 
                 ″+++″ 
               
               
                   
               
               
                 131 
                 VLIEETDQL 
                 ″++″ 
               
               
                   
               
               
                 132 
                 VLQDQVDEL 
                 ″++″ 
               
               
                   
               
               
                 133 
                 ALEELTGFREL 
                 ″++″ 
               
               
                   
               
               
                 134 
                 ALGRLGILSV 
                 ″+++″ 
               
               
                   
               
               
                 135 
                 ALTGLQFQL 
                 ″+++″ 
               
               
                   
               
               
                 136 
                 FIFGIVHLL 
                 ″+++″ 
               
               
                   
               
               
                 137 
                 FIQQERFFL 
                 ″+++″ 
               
               
                   
               
               
                 138 
                 NLINNIFEL 
                 ″++++″ 
               
               
                   
               
               
                 139 
                 FLASPLVAI 
                 ″++++″ 
               
               
                   
               
               
                 140 
                 FLFEDFVEV 
                 ″+++″ 
               
               
                   
               
               
                 141 
                 FLGELTLQL 
                 ″+++″ 
               
               
                   
               
               
                 142 
                 FLYEDSKSVRL 
                 ″+++″ 
               
               
                   
               
               
                 143 
                 TLHAVDVTL 
                 ″+++″ 
               
               
                   
               
               
                 144 
                 GLITQVDKL 
                 ″+++″ 
               
               
                   
               
               
                 145 
                 GLLHEVVSL 
                 ″+++″ 
               
               
                   
               
               
                 146 
                 GLLQQPPAL 
                 ″+++″ 
               
               
                   
               
               
                 147 
                 GLSEYQRNFL 
                 ″+++″ 
               
               
                   
               
               
                 148 
                 ICAGHVPGV 
                 ″+++″ 
               
               
                   
               
               
                 149 
                 ILNPVTTKL 
                 ″+++″ 
               
               
                   
               
               
                 150 
                 ILSEKEYKL 
                 ″+++″ 
               
               
                   
               
               
                 151 
                 ILVKQSPML 
                 ″+++″ 
               
               
                   
               
               
                 152 
                 KIMYTLVSV 
                 ″++″ 
               
               
                   
               
               
                 153 
                 KLLKGIYAI 
                 ″+++″ 
               
               
                   
               
               
                 154 
                 KLMNIQQQL 
                 ″+++″ 
               
               
                   
               
               
                 155 
                 KLMTSLVKV 
                 ″+++″ 
               
               
                   
               
               
                 156 
                 KMLEDDLKL 
                 ″+++″ 
               
               
                   
               
               
                 157 
                 KVLEFLAKV 
                 ″+++″ 
               
               
                   
               
               
                 158 
                 KVQDVLHQV 
                 ″+++″ 
               
               
                   
               
               
                 159 
                 LLLSDSGFYL 
                 ″+++″ 
               
               
                   
               
               
                 160 
                 LLPPPSPAA 
                 ″+++″ 
               
               
                   
               
               
                 161 
                 NLMLELETV 
                 ″+++″ 
               
               
                   
               
               
                 162 
                 RLADLKVSI 
                 ″++++″ 
               
               
                   
               
               
                 163 
                 SIFDAVLKGV 
                 ″++++″ 
               
               
                   
               
               
                 164 
                 SLFDGAVISTV 
                 ″+++″ 
               
               
                   
               
               
                 165 
                 KLLEEIEFL 
                 ″+++″ 
               
               
                   
               
               
                 167 
                 SLFSITKSV 
                 ″+++″ 
               
               
                   
               
               
                 168 
                 SLLSPLLSV 
                 ″+++″ 
               
               
                   
               
               
                 169 
                 SSLEENLLHQV 
                 ″+++″ 
               
               
                   
               
               
                 171 
                 TLLDVISAL 
                 ″++++″ 
               
               
                   
               
               
                 172 
                 TLQDSLEFI 
                 ″++++″ 
               
               
                   
               
               
                 173 
                 VILDSVASV 
                 ″++++″ 
               
               
                   
               
               
                 174 
                 VLVEITDVDFAA 
                 ″++++″ 
               
               
                   
               
               
                 175 
                 VMESILLRL 
                 ″+++″ 
               
               
                   
               
               
                 176 
                 YLHIYESQL 
                 ″+++″ 
               
               
                   
               
               
                 177 
                 YLYEAEEATTL 
                 ″+++″ 
               
               
                   
               
               
                 178 
                 YVLQGEFFL 
                 ″+++″ 
               
               
                   
               
               
                 179 
                 FVDTNLYFL 
                 ″+++″ 
               
               
                   
               
               
                 180 
                 GILQLVESV 
                 ″+++″ 
               
               
                   
               
               
                 181 
                 LLFDQNDKV 
                 ″+++″ 
               
               
                   
               
               
                 182 
                 LLPPPPPVA 
                 ″++++″ 
               
               
                   
               
               
                 183 
                 VLFETVLTI 
                 ″+++″ 
               
               
                   
               
               
                 184 
                 AVLGTSWQL 
                 ″+++″ 
               
               
                   
               
               
                 185 
                 FIAQLNNVEL 
                 ″+++″ 
               
               
                   
               
               
                 186 
                 FLDVSRDFV 
                 ″++″ 
               
               
                   
               
               
                 187 
                 FLNSFVFKM 
                 ″++″ 
               
               
                   
               
               
                 188 
                 GLEDEMYEV 
                 ″++″ 
               
               
                   
               
               
                 189 
                 SLSHLVPAL 
                 ″+++″ 
               
               
                   
               
               
                 190 
                 GLIELVDQL 
                 ″+++″ 
               
               
                   
               
               
                 191 
                 GLSDISAQV 
                 ″+++″ 
               
               
                   
               
               
                 192 
                 GMAAEVPKV 
                 ″++″ 
               
               
                   
               
               
                 193 
                 SLADSMPSL 
                 ″++″ 
               
               
                   
               
               
                 194 
                 SLAPFDREPFTL 
                 ″++″ 
               
               
                   
               
               
                 195 
                 ALIPDLNQI 
                 ″+++″ 
               
               
                   
               
               
                 197 
                 YLLTDNVVKL 
                 ″++″ 
               
               
                   
               
               
                 198 
                 GLLSAVSSV 
                 ″+++″ 
               
               
                   
               
               
                 199 
                 SLNSTTWKV 
                 ″+++″ 
               
               
                   
               
               
                 200 
                 YLLDFEDRL 
                 ″++++″ 
               
               
                   
               
               
                 201 
                 YLNISQVNV 
                 ″+++″ 
               
               
                   
               
               
                 202 
                 ALAAGGYDV 
                 ″++″ 
               
               
                   
               
               
                 203 
                 ILDTIFHKV 
                 ″+++″ 
               
               
                   
               
               
                 204 
                 RLCDIVVNV 
                 ″++″ 
               
               
                   
               
               
                 205 
                 TLFYESPHL 
                 ″+++″ 
               
               
                   
               
               
                 206 
                 SAVSGQWEV 
                 ″++″ 
               
               
                   
               
               
                 207 
                 GLVGLLEQA 
                 ″++++″ 
               
               
                   
               
               
                 208 
                 FLAVSLPLL 
                 ″+++″ 
               
               
                   
               
               
                 209 
                 FLLDTISGL 
                 ″+++″ 
               
               
                   
               
               
                 210 
                 FLAEQFEFL 
                 ″+++″ 
               
               
                   
               
               
                 211 
                 FIDDLFAFV 
                 ″+++″ 
               
               
                   
               
               
                 212 
                 FLIGQGAHV 
                 ″+++″ 
               
               
                   
               
               
                 213 
                 YINEDEYEV 
                 ″++″ 
               
               
                   
               
               
                 214 
                 FLFDGSMSL 
                 ″+++″ 
               
               
                   
               
               
                 215 
                 QLFEEEIEL 
                 ″++″ 
               
               
                   
               
               
                 216 
                 KVVSNLPAI 
                 ″++″ 
               
               
                   
               
               
                 217 
                 AQFGAVLEV 
                 ″+++″ 
               
               
                   
               
               
                 218 
                 ALDQFLEGI 
                 ″+++″ 
               
               
                   
               
               
                 219 
                 ALLELENSV 
                 ″++″ 
               
               
                   
               
               
                 220 
                 FLAEAPTAL 
                 ″++″ 
               
               
                   
               
               
                 221 
                 FLAPDNSLLLA 
                 ″++++″ 
               
               
                   
               
               
                 222 
                 FLIETGTLL 
                 ″+++″ 
               
               
                   
               
               
                 223 
                 FLQDIPDGLFL 
                 ″++″ 
               
               
                   
               
               
                 224 
                 FLSPLLPLL 
                 ″++″ 
               
               
                   
               
               
                 226 
                 GVIDPVPEV 
                 ″++″ 
               
               
                   
               
               
                 227 
                 IIAEGIPEA 
                 ″++″ 
               
               
                   
               
               
                 228 
                 IIAEYLSYV 
                 ″++″ 
               
               
                   
               
               
                 229 
                 ILSPWGAEV 
                 ″++++″ 
               
               
                   
               
               
                 230 
                 IMDDDSYGV 
                 ″++″ 
               
               
                   
               
               
                 231 
                 IVMGAIPSV 
                 ″+++″ 
               
               
                   
               
               
                 232 
                 KVMEGTVAA 
                 ″++″ 
               
               
                   
               
               
                 233 
                 MLEVHIPSV 
                 ″+++″ 
               
               
                   
               
               
                 234 
                 NLQRTVVTV 
                 ″++″ 
               
               
                   
               
               
                 235 
                 SLDVYELFL 
                 ″+++″ 
               
               
                   
               
               
                 236 
                 SLFDGFFLTA 
                 ″++++″ 
               
               
                   
               
               
                 237 
                 YLDRLIPQA 
                 ″+++″ 
               
               
                   
               
               
                 238 
                 YQYGAVVTL 
                 ″+++″ 
               
               
                   
               
               
                 239 
                 VLIDDTVLL 
                 ″+++″ 
               
               
                   
               
               
                 240 
                 ALVPTPALFYL 
                 ″+++″ 
               
               
                   
               
               
                 241 
                 FIPDFIPAV 
                 ″++″ 
               
               
                   
               
               
                 242 
                 GILDFZVFL 
                 ″++++″ 
               
               
                   
               
               
                 243 
                 GLPDLDIYL 
                 ″++++″ 
               
               
                   
               
               
                 244 
                 ILEPFLPAV 
                 ″+++″ 
               
               
                   
               
               
                 245 
                 KLIQLPVVYV 
                 ″+++″ 
               
               
                   
               
               
                 246 
                 KLPVPLESV 
                 ″+++″ 
               
               
                   
               
               
                 247 
                 KVLEMETTV 
                 ″+++″ 
               
               
                   
               
               
                 248 
                 NLLEQFILL 
                 ″+++″ 
               
               
                   
               
               
                 249 
                 VLLESLVEI 
                 ″++++″ 
               
               
                   
               
               
                 250 
                 VLTNVGAAL 
                 ″+++″ 
               
               
                   
               
               
                 251 
                 VLYELFTYI 
                 ″+++″ 
               
               
                   
               
               
                 252 
                 YLGDLIMAL 
                 ″+++″ 
               
               
                   
               
               
                 253 
                 YSDDDVPSV 
                 ″++++″ 
               
               
                   
               
               
                 254 
                 FLYSETWNI 
                 ″++++″ 
               
               
                   
               
               
                 255 
                 GMWNPNAPVFL 
                 ″++++″ 
               
               
                   
               
               
                 256 
                 ALQETPPQV 
                 ″+++″ 
               
               
                   
               
               
                 257 
                 FLQEWEVYA 
                 ″++++″ 
               
               
                   
               
               
                 258 
                 RIYPFLLMV 
                 ″+++″ 
               
               
                   
               
               
                 259 
                 TVLDGLEFKV 
                 ″++++″ 
               
               
                   
               
               
                 260 
                 RLDEAFDFV 
                 ″++++″ 
               
               
                   
               
               
                 261 
                 FLPETRIMTSV 
                 ″++++″ 
               
               
                   
               
               
                 262 
                 LMGPVVHEV 
                 ″++++″ 
               
               
                   
               
               
                 263 
                 GLMDNEIKV 
                 ″+++″ 
               
               
                   
               
               
                 264 
                 ILTGTPPGV 
                 ″+++″ 
               
               
                   
               
               
                 265 
                 ILWHFVASL 
                 ″++++″ 
               
               
                   
               
               
                 266 
                 QLTEMLPSI 
                 ″++++″ 
               
               
                   
               
               
                 267 
                 SLLETGSDLLL 
                 ″+++″ 
               
               
                   
               
               
                 268 
                 VLFPLPTPL 
                 ″++++″ 
               
               
                   
               
               
                 269 
                 VLQNVAFSV 
                 ″++++″ 
               
               
                   
               
               
                 270 
                 VVVDSDSLAFV 
                 ″++++″ 
               
               
                   
               
               
                 271 
                 YLLDQPVLEQRL 
                 ″++++″ 
               
               
                   
               
               
                 272 
                 KLDHTLSQI 
                 ″+++″ 
               
               
                   
               
               
                 273 
                 AILLPQPPK 
                 ″++″ 
               
               
                   
               
               
                 274 
                 KLLNLISKL 
                 ″++++″ 
               
               
                   
               
               
                 275 
                 KLMDLEDCAL 
                 ″++++″ 
               
               
                   
               
               
                 276 
                 NMISYVVHL 
                 ″++″ 
               
               
                   
               
               
                 277 
                 FLIDLNSTHGTFL 
                 ″+++″ 
               
               
                   
               
               
                 278 
                 FLLFINHRL 
                 ″+++″ 
               
               
                   
               
               
                 279 
                 NLAGENILNPL 
                 ″+++″ 
               
               
                   
               
               
                 280 
                 SLLNHLPYL 
                 ″++++″ 
               
               
                   
               
               
                 281 
                 TLQTVPLTTV 
                 ″++++″ 
               
               
                   
               
               
                 282 
                 YLLEQGAQV 
                 ″++++″ 
               
               
                   
               
               
                 283 
                 ALMPVTPQA 
                 ″+++″ 
               
               
                   
               
               
                 284 
                 KLQEQIHRV 
                 ″+++″ 
               
               
                   
               
               
                 285 
                 SITAVTPLL 
                 ″+++″ 
               
               
                   
               
               
                 286 
                 HLTEDTPKV 
                 ″+++″ 
               
               
                   
               
               
                 287 
                 ILMGHSLYM 
                 ″++++″ 
               
               
                   
               
               
                 288 
                 RLAPEIVSA 
                 ″+++″ 
               
               
                   
               
               
                 289 
                 SLLAANNLL 
                 ″++++″ 
               
               
                   
               
               
                 290 
                 IASPVIAAV 
                 ″+++″ 
               
               
                   
               
               
                 291 
                 KIIDTAGLSEA 
                 ″+++″ 
               
               
                   
               
               
                 292 
                 KLINSQISL 
                 ″+++″ 
               
               
                   
               
               
                 293 
                 GLAMVEAISYV 
                 ″++++″ 
               
               
                   
               
               
                 294 
                 KLYGPEGLELV 
                 ″++++″ 
               
               
                   
               
               
                 295 
                 SLAAVSQQL 
                 ″+++″ 
               
               
                   
               
               
                 296 
                 FILEPLYKI 
                 ″++++″ 
               
               
                   
               
               
                 297 
                 ILQNGLETL 
                 ″+++″ 
               
               
                   
               
               
                 298 
                 ALTDVILCV 
                 ″++++″ 
               
               
                   
               
               
                 299 
                 RLLEEEGVSL 
                 ″+++″ 
               
               
                   
               
               
                 300 
                 IVLERNPEL 
                 ″+++″ 
               
               
                   
               
               
                 301 
                 LQFDGIHVV 
                 ″+++″ 
               
               
                   
               
               
                 302 
                 SLAELDEKISA 
                 ″+++″ 
               
               
                   
               
               
                 303 
                 FVWEASHYL 
                 ″++++″ 
               
               
                   
               
               
                 304 
                 ALIRLDDLFL 
                 ″+++″ 
               
               
                   
               
               
                 305 
                 AMLAQQMQL 
                 ″+++″ 
               
               
                   
               
               
                 306 
                 AQVALVNEV 
                 ″+++″ 
               
               
                   
               
               
                 307 
                 FLLPVAVKL 
                 ″+++″ 
               
               
                   
               
               
                 308 
                 SLLDQIPEM 
                 ″+++″ 
               
               
                   
               
               
                 309 
                 SLSFVSPSL 
                 ″+++″ 
               
               
                   
               
               
                 310 
                 VMAEAPPGV 
                 ″+++″ 
               
               
                   
               
               
                 311 
                 YLHRQVAAV 
                 ″+++″ 
               
               
                   
               
               
                 314 
                 LIDDKGTIKL 
                 ″++″ 
               
               
                   
               
             
          
         
       
     
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