bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A044: Mutated NPM1 as target for immunotherapy of acute myeloid leukemia
Authors: Lee Dyantha I. van der , Reijmers Rogier M. , Honders M. Willy , Hagedoorn Renate S. , Jong Rob. M. de , Kester Michel G.D. , Steen Dirk M. van der , Ru Arnoud H. de , Kweekel Christiaan , Jedema Inge , Veelken Hendrik , Heemskerk Mirjam M. , Veelen Peter A. van , Falkenburg J.H. Frederik , Griffioen Marieke 
Published: February 2019

Abstract
The most frequent subtype of acute myeloid leukemia (AML) is defined by mutations in the nucleophosmin (NPM1) gene. Mutated NPM1 is an attractive target for immunotherapy, since it is an essential driver gene and 4 base pair frameshift insertions in exon 12 occur in 30-35% of AML, resulting in a novel C-terminal alternative reading frame of 11 amino acids. By searching in the HLA class I ligandome of primary AML, we identified multiple peptides derived from mutated NPM1. For one of these peptides, i.e., HLA-A*02:01-presented CLAVEEVSL, we searched for specific T-cells in AML patients and healthy individuals using peptide-MHC tetramers. Tetramer-positive CD8 T-cell clones were isolated and analyzed for reactivity against primary AML with mutated NPM1. From one selected clone with superior antitumor reactivity, we isolated the T-cell receptor (TCR) and demonstrated specific recognition and lysis of HLA-A*02:01-positive AML with mutated NPM1 in vitro after retroviral transfer to CD8 and CD4 T-cells. In vivo antitumor efficacy of TCR-transduced CD8 and CD4 T-cells was confirmed in immunodeficient mice engrafted with a human AML cell line expressing mutated NPM1. These data show that mutated NPM1-derived peptides are presented on AML and that CLAVEEVSL is a neoantigen that can be efficiently targeted on AML with mutated NPM1 by TCR gene transfer in a co-receptor independent fashion. Immunotherapy targeting mutated NPM1 may therefore contribute to treatment of AML.
Citation Format: Dyantha I. van der Lee, Rogier M. Reijmers, M. Willy Honders, Renate S. Hagedoorn, Rob. M. de Jong, Michel G.D. Kester, Dirk M. van der Steen, Arnoud H. de Ru, Christiaan Kweekel, Inge Jedema, Hendrik Veelken, Mirjam M. Heemskerk, Peter A. van Veelen, J.H. Frederik Falkenburg, Marieke Griffioen. Mutated NPM1 as target for immunotherapy of acute myeloid leukemia [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A044.
Abstract A062: TIM-3 plays distinct roles in different immune cells to regulate antitumor immune responses
Authors: Dai Jie , Pei Jerry , Mohrs Markus , Thurston Gavin , Ioffe Ella 
Published: February 2019

Abstract
T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) was originally identified as an inhibitory receptor that is expressed on Th1 T-cells to dampen T-cell immunity upon interaction with several putative ligands. The inhibitory role of TIM-3 is supported by multiple preclinical disease models, such as viral and bacterial infections, experimental autoimmune encephalitis, and allograft rejection. Recent evidence suggests that induction of TIM-3 expression on T-cells may promote resistance to cancer immunotherapy, including in response to treatment with PD-1/PD-L1 inhibitors. Thus, TIM-3 represents a putative novel immuno-oncology target. Here we report that in naïve mice TIM-3 is absent on T-cells, but is constitutively expressed on myeloid cells, including dendritic cells and macrophages. In tumor-bearing mice, TIM-3 expression is highly enriched on PD-1 positive CD4 and CD8 T-cells in the tumor microenvironment, but not on T-cells in draining lymph nodes or peripheral blood. Prophylactic or therapeutic treatment with anti-PD-1 blocking antibody delays tumor growth in wild-type mice. However, unexpectedly, TIM-3 genetic deficiency reduced overall survival of tumor-bearing mice treated with anti-PD-1 compared to wild-type control mice. Using a series of in vitro functional cell-based assays, we found that blocking TIM-3 function by either genetic knock-out or an inhibitory Ab increased proliferation of, and IFN-γ production by, effector CD8 T-cells following direct antigen stimulation. By contrast, TIM-3 gene knockout in bone marrow-derived macrophages did not impact responses to stimulation with Toll-like receptor ligands, and TIM-3 blockade reduced phagocytosis of apoptotic tumor cells by a macrophage cell line. Taken together, our results suggest TIM-3 may play opposite roles in T-cells and macrophages (inhibitory vs activating, respectively), and highlight the pleiotropic roles of TIM-3 in different immune cells in tumor immunology.
Citation Format: Jie Dai, Jerry Pei, Markus Mohrs, Gavin Thurston, Ella Ioffe. TIM-3 plays distinct roles in different immune cells to regulate antitumor immune responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A062.
Abstract A070: Virotherapy eradicates established melanoma by reprogramming the tumor microenvironment and engaging the adaptive immunity
Authors: Flatz Lukas , Ring Sandra , Bomze David , Onder Lucas , Cupovic Jovana , Schmidt Sarah , Orlinger Klaus , Besse Andrej , Besse Lenka , Driessen Christoph , Cheng Hung-Wei , Lercher Alexander , Speiser Daniel , Bald Tobias , Bergthaler Andreas , Ludewig Burkhard 
Published: February 2019

Abstract
Immunotherapy revolutionized the treatment of cancer patients. However, the lack of tumor specific T-cells and the immunosuppressive tumor microenvironment remain the major obstacles in curing treatment-resistant tumors. Here, we show that a novel, propagating noncytopathic virotherapy expressing the tumor-associated antigen TRP2 can eradicate established tumors. Interestingly, this was dependent on the route of treatment. Systemic administration of gene-based virotherapy induced a high number of tumor-infiltrating TRP2 specific CD8+ T-cells but was not able to cure established tumors. Moreover, localized tumor therapy in the periphery cured also distant metastasis in the lung, indicating that the locally induced immune response generates a systemic antitumor effect. Localized virotherapy predominantly infects tumor cells and tumor-associated fibroblasts, resulting in a proinflammatory reprogramming of the tumor microenvironment. Our data reveal that this immune activation is dependent on type I IFN signaling on the host but not on the tumor cell. These results have important clinical implications: i) our data explain why T-cell transfer or T-cell vaccines alone do not cure established tumors; ii) intratumoral gene-based cancer vaccination is superior to systemic treatment; and iii) a successful local antitumor response is associated with an efficient systemic antitumor response. Directly cancer targeting noncytopathic gene-based vaccines may be a promising approach by simultaneously supercharging the suppressive tumor microenvironment and inducing an adaptive immune response against selected tumor antigens.
Citation Format: Lukas Flatz, Sandra Ring, David Bomze, Lucas Onder, Jovana Cupovic, Sarah Schmidt, Klaus Orlinger, Andrej Besse, Lenka Besse, Christoph Driessen, Hung-Wei Cheng, Alexander Lercher, Daniel Speiser, Tobias Bald, Andreas Bergthaler, Burkhard Ludewig. Virotherapy eradicates established melanoma by reprogramming the tumor microenvironment and engaging the adaptive immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A070.
Abstract A077: Microenvironmental factors shape resistance patterns to immune checkpoint blockade
Authors: Gu Shengquing Stan , Hu Xihao Sherlock , Wang Xiaoqing Shawn , Li Ziyi , Traugh Nicole , Bu Xia , Xing Xiaofang , Freeman Gordon , Brown Myles , Liu Xiaole Shirley 
Published: February 2019

Abstract
Immune checkpoint blockade (ICB) therapy has dramatically improved the prognosis of several types of cancer. However, only a small proportion of patients respond. Although multiple biomarkers/mechanisms of resistance to ICB have been identified, it remains elusive to what extent the cellular/molecular mechanisms contribute to the heterogeneity of ICB response. To this end, we applied clonal barcoding for lineage tracing of cancer cells following control IgG or ICB treatment in a transplantation mouse model. We identified significant clonal heterogeneity within cancer cells in response to ICB, suggestive of a minority of pre-existing ICB-resistant clones prior to treatment. Furthermore, counter-intuitively, ICB-responding tumors harbored a higher proportion of ICB-resistant clones than nonresponding tumors post-treatment, indicating that the tumor microenvironment might dictate the initial response to ICB. Integrated gene expression and immune repertoire analyses of the tumor microenvironment identified more T-cell and B cell infiltration in the ICB responders, and found that BCR class switch is associated with ICB response. Our study established a system to assess the contributions of cancer cell-intrinsic and microenvironmental factors in response to ICB treatment, and identified B cell infiltration and repertoire constitution as a novel biomarker for ICB response.
Citation Format: Shengquing Stan Gu, Xihao Sherlock Hu, Xiaoqing Shawn Wang, Ziyi Li, Nicole Traugh, Xia Bu, Xiaofang Xing, Gordon Freeman, Myles Brown, Xiaole Shirley Liu. Microenvironmental factors shape resistance patterns to immune checkpoint blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A077.
Abstract A097: Complement system mutations in cancer: Uncovering new relationships between tumor hypoxia and complement
Authors: Olcina Monica M. , Balanis Nikolas G. , Kim Ryan K. , Thompson Michael J. , Graeber Thomas G. , Giaccia Amato J. 
Published: February 2019

Abstract
The complement system has been proposed to facilitate cancer hallmarks such as increased metastatic potential, proliferation and apoptosis evasion. Despite the association between complement and tumor progression, a detailed characterization of cancer genetic alterations in the complement system has not been performed to date. Here, we report a number of previously unappreciated mutations in complement system genes. Taken together as a pathway, mutations in complement genes occur at a relatively high frequency and across a number of cancer types. Notably, when grouping complement mutations into functionally relevant subgroups according to gene function, mutations and copy number alterations in genes within these subgroups are associated with changes in overall survival outcomes in a range of cancers. We use specific complement component mutations in colorectal cancer to uncover and experimentally validate crosstalk between complement and hypoxia, providing new associations between this innate immunity pathway and a prevalent component of the tumor microenvironment. Our data highlight the complex mechanism employed by cancers to manipulate the innate immune system and point to the potential use of complement system mutations in successful patient stratification into clinically and biologically relevant groups.
Citation Format: Monica M. Olcina, Nikolas G. Balanis, Ryan K. Kim, Michael J. Thompson, Thomas G. Graeber, Amato J. Giaccia. Complement system mutations in cancer: Uncovering new relationships between tumor hypoxia and complement [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A097.
Abstract A102: Rescue of lost skin dendritic cells in melanoma is key for the resuscitation of antitumor T-cell responses
Authors: Prokopi Anastasia , Tripp Christoph H. , Tummers Bart , Komenda Kerstin , Hutter Katharina , Cappellano Giuseppe , Bellmann Lydia , Efremova Mirjana , Trajanoski Zlatko , Chen Suzie , Clausen Bjorn E. , Green Douglas R. , Stoitzner Patrizia 
Published: February 2019

Abstract
One major characteristic of skin-related cancers is the loss of skin-resident dendritic cell populations. In the tg(Grm1)EPv mouse model, ectopic expression of the metabotropic glutamate receptor-1 in melanocytes leads to a highly proliferative and antiapoptotic phenotype, resulting in melanoma formation within the dermis. The slow progression of these tumors allows for the in depth analysis of the immune infiltrate in growing tumors. We here show that total DCs (CD11c+ cells) are gradually lost as the tumor progresses. Mainly the dermal CD11b+ DCs are affected, whereas epidermal Langerhans cells remain unchanged. We hypothesized that extrinsic cell death of the DCs may be induced within the growing tumor. Indeed, the tumor tissue upregulated the expression of Fas ligand (FasL) that can induce extrinsic apoptosis in immature DCs that express Fas (CD95). Fas-mediated apoptosis depends on the activation of caspase-8 and mice in which the autoproteolytic cleavage site D387 is mutated to alanine (casp8D387A/casp8D387A) show strong resistance to Fas-mediated death. We compared the apoptosis induction in the different DC subsets in casp8WT/casp8WT and in casp8D387A/casp8D387A upon intradermal administration of an agonistic anti-CD95 antibody and we found that, indeed, CD11b+ DCs in WT mice are susceptible to apoptosis via CD95. In order to retrieve the intratumoral DCs, we treated tg(Grm1)EPv mice carrying tumor lesions with Flt3L and the percentages of the CD11b+ subset could be restored back to the levels of tumor-free mice. At the same time, T-cells from both the tumor and the tumor-draining lymph node were able to produce more cytotoxic cytokines. Our data thus indicate that the loss of DCs in melanoma depends on induction of apoptosis within the tumor; rescue of skin DCs may be a promising strategy in order to enhance the efficacy of existing immunotherapeutic strategies against skin-related cancers.
Citation Format: Anastasia Prokopi, Christoph H. Tripp, Bart Tummers, Kerstin Komenda, Katharina Hutter, Giuseppe Cappellano, Lydia Bellmann, Mirjana Efremova, Zlatko Trajanoski, Suzie Chen, Bjorn E. Clausen, Douglas R. Green, Patrizia Stoitzner. Rescue of lost skin dendritic cells in melanoma is key for the resuscitation of antitumor T-cell responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A102.
Abstract A106: Higher numbers of cancer stem cells in the peripheral blood of children with B-ALL after chemotherapy
Authors: Salem Mohamed Labib , Attia Mohamed , Abdou Said , Zidan Abdel-Aziz A. , Zidan Mona F. 
Published: February 2019

Abstract
Background: Acute lymphocytic leukemia (ALL) is biologically and clinically considered as a heterogeneous neoplasm of lymphoid progenitor cells in the bone marrow (BM). 15- 20 % of children with ALL who achieve an initial remission, will show relapse. One potential mechanism behind this relapse could be the emergence of cancer stem cells (CSCs), which are considered the driving force of tumorigenesis due to their ability of self-renewal as well as the emergence of immune regulatory cells including myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Treg). Aim: The main aim of this study was to analyze the numbers of CSCs and correlate these numbers with the numbers of blasT-cells, MDSCs and Treg cells in children with B-ALL before and after induction of chemotherapy. Materials and Methods: CSCs were defined as CD45dimCD19+CD10+CD34+CD38-, MDSCs were defined as Lin-HLA-DR-CD33+CD11b+ and Treg cells were defined as CD4+CD25+CD127-. The frequencies of these cells were analyzed in the peripheral blood of B-ALL patients before (n= 10) and after (n= 10) induction of chemotherapy using flow cytometry. Results: Significant increases in the numbers of CSCs were shown in B-ALL patients after induction of chemotherapy as compared to newly diagnosed patients (7.6± 8.3 vs. 2.7± 2.4, P&lt;0.05). The numbers of CSCs in ALL patents before and after induction of chemotherapy inversely correlated with the numbers of the blasT-cells. Additionally, the numbers of MDSCs and Treg cells were higher and lower, respectively, in patients after induction of chemotherapy as compared to before chemotherapy. Conclusion: Our results indicate that chemotherapy of B-ALL patients results in emergence of high numbers of CSCs and MDSCs, which might be contributing, respectively, to tumor relapse and creation of systemic immune suppression. This pilot study opens a new avenue to investigate the mechanism mediating the emergence of these cells on larger population of B-ALL patients at different treatment stages.
Citation Format: Mohamed Labib Salem, Mohamed Attia, Said Abdou, Abdel-Aziz A. Zidan, Mona F. Zidan. Higher numbers of cancer stem cells in the peripheral blood of children with B-ALL after chemotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A106.
Abstract A142: Anti-mesothelin immunotoxins induce markers of immunogenic cell death and when injected locally into AE17M mesothelioma tumors enhance the effect of CTLA-4 blockade
Authors: Leshem Yasmin , King Emily , Reiter Yoram , Pastan Ira 
Published: February 2019

Abstract
Background: SS1P and LMB-100 are anti-mesothelin immunotoxins composed of a targeting antibody fragment genetically fused to a truncated pseudomonas exotoxin A. We have previously repotrted a synergistic antitumor effect when SS1P or LMB-100 were injected locally into tumors of murine breast cancer in combination with antibodies that block the immune check point CTLA-4. In this study our goal is to explore if this treatment can be applied in a murine mesothelioma model. Method: The mouse mesothelioma AE17M cell line, expressing human mesothelin, was treated in culture with anti-mesothelin immunotoxins. We collected data on the cytotoxic activity and ability to induce markers of immunogenic cell death. In vivo effects were performed on AE17M tumors growing in C57/Bl6 mice. Results: AE17M cells are sensitive to both SS1P and LMB-100 in culture, but when injected IV, the immunotoxins did not affect AE17M tumor growth rate. To overcome obstacles in drug penetration we injected immunotoxins directly into AE17M tumors and found that they only increased the survival of mice from 16 days to 20 days. In addition, anti-CTLA-4 monotherapy failed to control AE17M tumor growth rate in most mice. But when locally injected SS1P or LMB-100 was combined with i.p. anti-CTLA-4, tumor regressions occurred and the median survival increased to 80 days or longer. In search for possible mechanisms enabling immunotoxins to contribute to anti-CTLA-4 activity, we examined their ability to induce markers of immunogenic cell death. We found that both LMB-100 and SS1P increased release of ATP from AE17M cells. In addition, LMB-100 induced calreticulin expression on the surface of both AE17M cells and KLM-1 cells. These results point to possible pathways allowing immunotoxins to promote anti-tumor immunity and sensitize tumors for anti-CTLA-4 effect. Conclusion: Our findings in the AE17M model provide additional support for the use of local immunotoxins in combination with anti-CTLA-4.
Citation Format: Yasmin Leshem, Emily King, Yoram Reiter, Ira Pastan. Anti-mesothelin immunotoxins induce markers of immunogenic cell death and when injected locally into AE17M mesothelioma tumors enhance the effect of CTLA-4 blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A142.
Abstract A146: Systematic discovery of immune regulatory mechanisms in tumor cells
Authors: Pan Deng , Kobayashi Aya , Jiang Peng , Yuan Guo-Cheng , Liu X. Shirley , Doench John , Qiu Xintao , Rao Prakash , Long Henry , Brown Myles A. , Wucherpfennig Kai W. , Andrade Lucas Ferrari de , Tay Rong En , Luoma Adrienne M. , Tsoucas Daphne , Lim Klothilda 
Published: February 2019

Abstract
Many human cancers are resistant to immunotherapy for reasons that are poorly understood. We used a genome-scale CRISPR/Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T-cells, the central effectors of antitumor immunity. Inactivation of &gt;100 genes sensitized mouse B16F10 melanoma cells to killing by T-cells, including Pbrm1, Arid2 and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T-cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T-cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T-cells.
Citation Format: Deng Pan, Aya Kobayashi, Peng Jiang, Guo-Cheng Yuan, X. Shirley Liu, John Doench, Xintao Qiu, Prakash Rao, Henry Long, Myles A. Brown, Kai W. Wucherpfennig, Lucas Ferrari de Andrade, Rong En Tay, Adrienne M. Luoma, Daphne Tsoucas, Klothilda Lim. Systematic discovery of immune regulatory mechanisms in tumor cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A146.