bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B017: A soluble form of CD80 inhibits PD-L1 immune suppression and stimulates T cells through CD28-specific pathways indicating potential for increased therapeutic activity over checkpoint inhibition alone
Authors: Long Tiha M. , Ostrand-Rosenberg Suzanne 
Published: May 2016

Abstract
Antibodies that block the PD-1/PD-L1 pathway have demonstrated therapeutic success against several cancer types, but do not induce a response in the majority of patients. The development of treatments that provide activation signals to T cells by targeting co-stimulatory receptors, in addition to checkpoint inhibition, may increase anti-tumor immunity and the percent of responding patients. CD80/B7-1 is a co-stimulatory molecule that also interacts with PD-L1. CD80 is expressed by antigen presenting cells and ligates to CD28 providing co-stimulation during T cell activation. Furthermore, PD-L1 interacts with T cell CD80 in a reverse signaling pathway that promotes T cell anergy. The ability of CD80 to block inhibitory and promote stimulatory signaling pathways in T cell activation suggests potential therapeutic value. We have shown that soluble CD80 fused to the Fc region of IgG (CD80-Fc) blocks PD-1/PD-L1 interactions thus restoring activation of CD4+ and CD8+ T cells. Moreover, CD80-Fc was more effective in vitro than PD-1/PD-L1 monoclonal antibodies at restoring T cell activation, which suggests that CD80-Fc may be stimulating CD28 in addition to blocking PD-1/PD-L1 signaling. Stimulation of T cell CD28 in the absence of other signals induces downstream transcription, and signaling pathway activation. In fact, agonist CD28 antibody can induce functions in T cells in both naïve and activated cells, even in the absence of TCR activation. We now demonstrate that CD80-Fc does indeed stimulate T cells via CD28 activation by demonstrating comparable downstream results of CD80-Fc and agonist CD28 antibody treatment of both human and mouse T cells. Therefore, CD80-Fc may provide a novel therapeutic approach to target T cell checkpoint inhibition in addition to providing stimulatory signaling to improve T cell activation and anti-tumor immunity.
Citation Format: Tiha M. Long, Suzanne Ostrand-Rosenberg. A soluble form of CD80 inhibits PD-L1 immune suppression and stimulates T cells through CD28-specific pathways indicating potential for increased therapeutic activity over checkpoint inhibition alone. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B017.
Abstract B030: Structure-function studies of cytosolic DNA sensing pathway
Authors: Gao Pu , Ascano Manuel , Zillinger Thomas , Barchet Winfried , Tuschl Thomas , Patel Dinshaw J. 
Published: May 2016

Abstract
The appearance of DNA in the cytoplasm is a very dangerous signal to cells. This could be caused by viral or bacterial infection, or as a result of cellular damage that leaks host DNA into the cytoplasm. Cytosolic DNA activates the host immune response, which is critically dependent on the newly identified cGAS-cGAMP-STING pathway. Structure-function studies from our laboratories have demonstrated that upon dsDNA binding, cGAS is activated through conformational transitions, resulting in formation of a catalytically competent and accessible nucleotide-binding pocket for generation of c[G(2',5')pA(3',5')p]. Further, cyclization occurs in a stepwise manner through initial generation of 5'-pppG(2',5')A prior to cyclization to c[G(2',5')pA(3',5')p], with the latter positioned precisely in the catalytic pocket. These studies established c[G(2',5')pA(3',5')p] as a founding member of a family of metazoan 2',5'-containing cyclic heteronucleotide second messengers distinct from bacterial 3',5' cyclic dinucleotides. Follow up structure-function studies from our laboratories have shown that human and mouse STING undergo an ‘open’ to ‘closed’ conformational transition upon binding c[G(2',5')pA(3',5')p] and the anti-viral agent DMXAA. Comparing hSTING to mSTING in cellular assays, 2',5'-linkage-containing cGAMP isomers were more specific triggers of the IFN pathway compared to the all 3',5'-linkage isomer counterparts. Our results highlight the critical role of the lid residue at position 230 (Gly in hSTING; Ile in mSTING) for the DMXAA species selectivity. Our structural and functional results also shed light on strategies to restore an efficient DMXAA-response of hSTING based on the binding pocket S162A and Q266I substitutions.
Citation Format: Pu Gao, Manuel Ascano, Thomas Zillinger, Winfried Barchet, Thomas Tuschl, Dinshaw J. Patel. Structure-function studies of cytosolic DNA sensing pathway. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B030.
Abstract B043: Suppression of T cell responses by androgen deprivation drug leads to early relapse
Authors: Pu Yang 
Published: May 2016

Abstract
Physical or chemical androgen deprivation therapy (ADT) is the cornerstone treatment for metastatic prostate cancer, but relapse eventually occurs and the results of combination of ADT with immunotherapy are disappointing. Here, we show that physical castration can synergize with subsequent immunotherapy while the more commonly used chemical ADT suppresses the immunological protection induced by immunotherapy. Furthermore, chemical ADT can broadly inhibit immune responses. Mechanistically, the inhibition of immune responses by chemical ADT targets T cells by interfering with initial T cell priming, independently of the androgen receptor. We have shown that this off-target immune suppression is mediated by a receptor shared by γ-aminobutyric acid. Further investigation of chemical ADT administered with immunotherapy has revealed that timing and dosing critically control anti-tumor effects. Therefore, this study highlights an underappreciated mechanism of ADT immune suppression and provides a new strategy to enhance immunity and prevent the relapse of advanced prostate cancer.
Citation Format: Yang Pu. Suppression of T cell responses by androgen deprivation drug leads to early relapse. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B043.
Abstract B073: Structural basis of the 12-23 rule in V(D)J recombination
Authors: Ru Heng , Chambers Melissa G. , Liao Maofu , Wu Hao 
Published: May 2016

Abstract
The V, D and J segment recombination (V(D)J recombination) is the key event in the development and maturation of T and B lymphocytes, which generates a diverse repertoire of T and B cell clones for the further selection of useful specificities. V(D)J recombination is also the basis for antibody diversity. The initiation step of V(D)J recombination is carried out by a pair of lymphocyte specific enzymes, which are called recombination-activating gene 1 and 2 (RAG1 and RAG2). RAG1 and RAG2 associate with each other and with two recognition signal sequences (RSS, 12RSS and 23RSS) adjacent to the coding ends of the V, D and J segments to catalyze the double stranded breaks required for joining. The reaction goes through several catalytic steps that result in formation of the single recombination complex (SC), the paired complex (PC), the cleaved signal complex (CSC) as well as the signal end complex (SEC).
In order to understand the mechanisms of how RAG complex functions on DNA, we solved the structures PC and CSC by cryo-electron microscopy near the atomic resolution. Compared with the Apo-RAG complex that constitutes an open conformation, the PC and CSC reveal a closed conformation with RAG1 in one protomer interacts with RAG2 in another protomer. Furthermore, the first nucleotide of the heptamer in the non-transfer strand is flipped out to avoid the steric hindrance of the 3'-OH to attack the phosphodiester bond in the transfer strand. Upon nucleophilic attack and hairpin formation, the nucleotide adjacent to the 5'-position of the attacked phosphate is also flipped out to accommodate the tensile force in the hairpin DNA. In addition, we found that the conformation changes in the nonamer-binding domain (NBD), which is distorted toward to the 12RSS, and the distorsion requires two turns for the nonamer DNA in the 23RSS to reach the NBD. Finally, we found that two HMGB1 molecules, rather than one, are required to bind and bend both 12RSS and 23RSS DNA to adjust the conformational change of NBD on each side. In summary, our structural models not only uncover the mechanisms of how RAG protein catalyzes the hairpin formation, but also provide the structural basis of the 12-23 rule in V(D)J recombination.
Citation Format: Heng Ru, Melissa G. Chambers, Maofu Liao, Hao Wu. Structural basis of the 12-23 rule in V(D)J recombination. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B073.
Abstract B104: Characterization and specificity analysis of tumor infiltrating lymphocytes in ovarian carcinoma
Authors: Peper Janet Kerstin , Röhle Kevin , Schuster Heiko , Wagner Philipp , Rammensee Hans-Georg , Stevanovic Stefan 
Published: May 2016

Abstract
Introduction: The great majority of patients suffering from ovarian cancer (OvCa) relapse after initial therapy, making OvCa the most lethal gynecological malignancy. The immunogenic nature of OvCa is highlighted by frequent infiltration with immune cells, which represent an independent prognostic factor in OvCa patients and argues in favor for the development of immunotherapies, including peptide-based cancer vaccines. The phenotype of OvCa infiltrating T cells as well as their specificity and expression of inhibitory receptors is so far unknown. This information is however critically important for the design of novel immunotherapies including the application of checkpoint inhibitor therapy.
Materials and Methods: Tumor infiltrating lymphocytes (TILs) were isolated from fresh tumor tissue of OvCa patients obtained during tumor debulking surgery. The phenotype and expression of inhibitory molecules LAG3, CTLA4, PD1 and TIM3 was assessed by flow cytometry. Peptide specificity of infiltrating T cells was analyzed by screening for reactivity against naturally presented HLA ligands employing IFNγ ELISPOT and flow cytometry. These natural presented HLA ligands have been originally identified by mass spectrometry in an extensive HLA ligandome analysis of OvCa samples.
Results: TILs from each analyzed OvCa sample demonstrated expression of at least one of the investigated inhibitory receptors. While LAG3 and PD1 were most prominent during this analysis, CTLA4 expression was only weak or absent. Furthermore, high amounts of effector memory, but few naive or central memory T cells were present. Notably, OvCa infiltrating CD4+ T cells and CD8+ T cells shared a similar expression pattern of inhibitory surface markers within each single patient. We further obtained first results in peptide-specificity of OvCa-derived T cells by screening them for reactivity against naturally presented HLA ligands identified on OvCa samples.
Conclusion: In summary, we provide first insight into the expression of various inhibitory receptors on OvCa infiltrating T cells and their peptide specificities.
Citation Format: Janet Kerstin Peper, Kevin Röhle, Heiko Schuster, Philipp Wagner, Hans-Georg Rammensee, Stefan Stevanovic. Characterization and specificity analysis of tumor infiltrating lymphocytes in ovarian carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B104.
Abstract B119: Deciphering CD20 immunogenicity to generate protective anti-tumor CD4+ and CD8+ T cells
Authors: Siberil Sophie , Milcent Benoit , Riller Quentin , Deligne Claire , Hamieh Mohamad , Toutirais Olivier , Latouche Jean-Baptiste , Teillaud Jean-Luc 
Published: May 2016

Abstract
We have previously shown that anti-tumor T cell response is triggered by anti-CD20-mAb in mice bearing EL4-huCD20 tumor cells, a murine tumor expressing human CD20+ (huCD20) molecule. To define huCD20-derived epitopes that might be targeted by mAb-induced adaptive responses, we have selected different candidate peptides restricted to Kb, Db, and I-Ab, based on in silico prediction and in vitro binding to recombinant MHC molecules. Naive C57Bl/6 mice were then immunized with different mixtures of these peptides and subsequently challenged with EL4-huCD20 tumor cells. A longer survival could be achieved in mice immunized with MHCI and MHCII huCD20-derived peptide mixtures corresponding to various regions of the human CD20 molecule. Then, we defined in the same regions twenty-three huCD20-derived peptides with high in vitro binding to human MHCI and MHCII molecules frequent in Caucasian populations. The use of humanized HLA-DR1/HLA-A2.1 transgenic mice injected with EL4-huCD20 tumor cells and of NIH/3T3 cells expressing accessory and human HLA-DR1 or A2.1 molecules loaded with the candidate peptides made it possible to define 4 MHCI-restricted and 13 MHCII-restricted CD20-derived peptides capable of stimulating IFN-gamma production by specific CD4+ and CD8+ T cells. These findings support further studies on the identification and characterization of CD20-specific T cells in anti-CD20-treated follicular lymphoma patients. The definition of CD20-derived immunogenic epitopes also paves the way for the search of new biomarkers correlating with the clinical outcome of patients.
Citation Format: Sophie Siberil, Benoit Milcent, Quentin Riller, Claire Deligne, Mohamad Hamieh, Olivier Toutirais, Jean-Baptiste Latouche, Jean-Luc Teillaud. Deciphering CD20 immunogenicity to generate protective anti-tumor CD4+ and CD8+ T cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B119.
Abstract B147: Randomized phase II trial of a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with recurrent prostate cancer (NCT01341652)
Authors: McNeel Douglas G. , Fong Lawrence , Antonarakis Emmanuel S. , Liu Glenn 
Published: May 2016

Abstract
Background: Patients with rapidly rising PSA alone after definitive therapy for prostate cancer are at high risk for metastatic progression and ultimately death from prostate cancer. This is a stage of disease for which there are no standard therapies, although androgen deprivation is often used. We have previously reported that a DNA vaccine encoding PAP (pTVG-HP) was safe and could elicit antigen-specific CD4+ and CD8+ T cells in this population (NCT00582140). Patients who developed persistent Th1-type immunity tended to have favorable changes in serum PSA doubling time. The safety, immunological activity, and changes in PSA doubling time were observed in a second pilot clinical trial evaluating different schedules of administration (NCT00849121).
Methods: 106 patients with high-risk PSA-recurrent prostate cancer, PSA doubling time &lt; 12 months, and no metastases by standard radiographic imaging, are being randomized to DNA vaccine with GM-CSF adjuvant versus GM-CSF adjuvant alone in this multicenter trial (NCT01341652). The primary endpoint is 2-year radiographic progression-free survival (PFS). Secondary and exploratory endpoints include median PFS, predictive and early response immune biomarkers, association of T-cell immunity with PFS, and change in tumor growth rates as measured by PSA and quantitative bone imaging using NaF PET imaging.
Results: To our knowledge, this is the first randomized, phase II trial using an anti-tumor DNA vaccine. Enrollment is ongoing, but expected to be complete in 2015. The clinical and biomarker plan of evaluation will be presented, as well as descriptions of other pilot clinical trials ongoing with this DNA vaccine.
Citation Format: Douglas G. McNeel, Lawrence Fong, Emmanuel S. Antonarakis, Glenn Liu. Randomized phase II trial of a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with recurrent prostate cancer (NCT01341652). [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B147.
Abstract B156: Tumor high endothelial venules (HEVs), specialized blood vessels which recruit lymphocytes to limit tumor progression
Authors: Laffont Robin , Lafouresse Fanny , Girard Jean-Philippe 
Published: May 2016

Abstract
We discovered that some blood vessels present within the tumor microenvironment can be associated with favorable prognosis by contributing to tumor suppression rather than tumor growth (Martinet and Girard, Cancer Res 2011). These specialized blood vessels, designated high endothelial venules (HEVs), are normally found in lymph nodes where they mediate lymphocyte entry (Girard et al., Nat Rev Immunol 2012). A high density of tumor HEVs in human tumors was associated with high levels of cytotoxic lymphocyte infiltration, indicating that HEVs may contribute to the eradication of tumors by facilitating access of ‘killer’ lymphocytes into tumor tissues. It is thus important to better define the mechanisms regulating HEV formation. Our previous data have revealed a critical role for dendritic cells (Moussion and Girard, Nature 2011). Here, we will present our most recent results indicating that tumor HEVs may be central to the control of tumor growth in mouse tumor models.
Citation Format: Robin Laffont, Fanny Lafouresse, Jean-Philippe Girard. Tumor high endothelial venules (HEVs), specialized blood vessels which recruit lymphocytes to limit tumor progression. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B156.
Abstract IA01: T cells as a drug for the personalized immunotherapy of cancer
Authors: Rosenberg Steven 
Published: May 2016

Abstract
Adoptive cell transfer (ACT) immunotherapy using T lymphocytes with antitumor activity is a living therapy that can be highly effective in patients with a variety of metastatic cancers. Naturally occurring tumor infiltrating lymphocytes (TIL) expanded in vitro and administered following a lymphodepleting preparative regimen mediated objective regression of metastatic melanoma in 56% of 194 patients including complete regressions in 20% of patients who remain ongoing disease-free 3 to 10 years later. Recent studies have shown that TIL recognized random somatic mutations that served as the targets resulting in complete cancer regressions. To extend ACT immunotherapy to additional patients we developed an approach based on deep exomic sequencing and immunologic testing to generate T cells that recognized immunogenic mutations in a variety of human cancer types including esophageal, colorectal, bile duct, gastric, pancreatic, ovarian and lung cancer. Targeting these unique mutations opens the possibility of using ACT to treat patients with common epithelial cancers. We used this approach to treat a patient with metastatic cholangiocarcinoma using autologous mutation-reactive T cells and mediated regression of lung and liver metastases ongoing at two years. In addition to the use of naturally occurring mutation-reactive cells, we have genetically engineered autologous lymphocytes to express antitumor T-cell receptors (TCR) or chimeric antigen receptors (CAR) for use in ACT immunotherapy. These cells can mediate durable cancer regressions in heavily pretreated patients with refractory lymphomas, sarcomas, and melanoma. Thus autologous T cells can be used to provide a highly personalized therapy for cancer patients refractory to conventional cancer treatments.
Citation Format: Steven Rosenberg. T cells as a drug for the personalized immunotherapy of cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA01.
Abstract IA02: Biology of the PD-1 pathway
Authors: Sharpe Arlene H. 
Published: May 2016

Abstract
The PD-1 co-inhibitory pathway is a key regulator of the critical balance between stimulatory and inhibitory signals needed for effective immune responses to microbes and tumors, as well as self-tolerance. This pathway consists of the inhibitory Programmed Death (PD)-1 receptor and its two ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273). PD-1 is inducibly expressed on T cells, and its ligands have distinct expression patterns. PD-L1 is broadly expressed on hematopoietic and non-hematopoietic cells, whereas PD-L2 is inducibly expressed primarily on DCs and macrophages. In this talk, mechanisms by which the PD-1:PD-L pathway regulates optimal immune homeostasis and tolerance will be discussed. In addition, the functions of the PD-1 pathway in controlling humoral immune responses will be discussed, and compared to the functions of CTLA-4 in regulating humoral immunity.
Citation Format: Arlene H. Sharpe. Biology of the PD-1 pathway. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA02.