Journal Articles

Innovative Methods

Methods with focus on improving cancer immunotherapy approaches

B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma

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Knowledge of PD-L1 expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might identify biomarkers that predict the efficacy of immunotherapy with anti-PD-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may also identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression. We found that PD-L1 expression, particularly in non-germinal center B cell-derived diffuse large B-cell lymphoma (DLBCL), is controlled and regulated by several interactive signaling pathways, including the B-cell receptor (BCR) and JAK2/STAT3 signaling pathways. We found in PD-L1-positive B-cell lymphoma cells that BCR-mediated NFATc1 activation up-regulates IL-10 chemokine expression. Released IL-10 activates the JAK2/STAT3 pathway, leading to STAT3-induced PD-L1 expression. IL-10 antagonist antibody abrogates IL-10/STAT3 signaling and PD-L1 protein expression. We also found that BCR pathway inhibition by BTK inhibitors (ibrutinib, acalabrutinib, and BGB-3111) blocks both NFATc1 and STAT3 activation, thereby inhibiting IL-10 and PD-L1 expression. Finally, we validated the PD-L1 signaling network in two primary DLBCL cohorts, consisting of 428 and 350 cases and showed significant correlations between IL-10, STAT3, and PD-L1. Thus, our findings reveal a complex signaling network regulating PD-L1 expression in B-cell lymphoma cells and suggest that PD-L1 expression can be modulated by small molecule inhibitors to potentiate immunotherapies.

Author Info: (1) Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, China. (2) Department of Hematopathology, The University of Texas MD Anderson Cancer Center

Author Info: (1) Department of Hematology, The Second Hospital of Dalian Medical University, Dalian, China. (2) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (3) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (4) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (5) Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China. (6) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (7) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (8) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (9) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (10) Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (11) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (12) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; lvpham@mdanderson.org.

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Antibody-Neutralized Reovirus Is Effective in Oncolytic Virotherapy

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Immunotherapy is showing promise for otherwise incurable cancers. Oncolytic viruses (OVs), developed as direct cytotoxic agents, mediate their antitumor effects via activation of the immune system. However, OVs also stimulate antiviral immune responses, including the induction of OV-neutralizing antibodies. Current dogma suggests that the presence of preexisting antiviral neutralizing antibodies in patients, or their development during viral therapy, is a barrier to systemic OV delivery, rendering repeat systemic treatments ineffective. However, we have found that human monocytes loaded with preformed reovirus-antibody complexes, in which the reovirus is fully neutralized, deliver functional replicative reovirus to tumor cells, resulting in tumor cell infection and lysis. This delivery mechanism is mediated, at least in part, by antibody receptors (in particular FcgammaRIII) that mediate uptake and internalization of the reovirus/antibody complexes by the monocytes. This finding has implications for oncolytic virotherapy and for the design of clinical OV treatment strategies. Cancer Immunol Res; 1-13. (c)2018 AACR.

Author Info: (1) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. (2) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United

Author Info: (1) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. (2) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. (3) Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands. (4) Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands. (5) Department of Immunology, Mayo Clinic, Rochester, Minnesota. (6) Department of Immunology, Mayo Clinic, Rochester, Minnesota. (7) Oncolytics Biotech Incorporated, Calgary, Alberta, Canada. (8) Leiden University Medical Centre, Department of Molecular Cell Biology, Leiden, the Netherlands. (9) Department of Immunology, Mayo Clinic, Rochester, Minnesota. (10) Institute of Cancer Research, London, United Kingdom. (11) Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom. e.ilett@leeds.ac.uk.

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CAR-T Cells Based on Novel BCMA Monoclonal Antibody Block Multiple Myeloma Cell Growth

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The cell-surface protein B cell maturation antigen (BCMA, CD269) has emerged as a promising target for CAR-T cell therapy for multiple myeloma. In order to create a novel BCMA CAR, we generated a new BCMA monoclonal antibody, clone 4C8A. This antibody exhibited strong and selective binding to human BCMA. BCMA CAR-T cells containing the 4C8A scFv were readily detected with recombinant BCMA protein by flow cytometry. The cells were cytolytic for RPMI8226, H929, and MM1S multiple myeloma cells and secreted high levels of IFN-gamma in vitro. BCMA-dependent cytotoxicity and IFN-gamma secretion were also observed in response to CHO (Chinese Hamster Ovary)-BCMA cells but not to parental CHO cells. In a mouse subcutaneous tumor model, BCMA CAR-T cells significantly blocked RPMI8226 tumor formation. When BCMA CAR-T cells were given to mice with established RPMI8226 tumors, the tumors experienced significant shrinkage due to CAR-T cell activity and tumor cell apoptosis. The same effect was observed with 3 humanized BCMA-CAR-T cells in vivo. These data indicate that novel CAR-T cells utilizing the BCMA 4C8A scFv are effective against multiple myeloma and warrant future clinical development.

Author Info: (1) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. robert.berahovich@promab.com. (2) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. huazhou369@gmail.com. (3) ProMab Biotechnologies

Author Info: (1) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. robert.berahovich@promab.com. (2) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. huazhou369@gmail.com. (3) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. shirley.xu@promab.com. (4) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. yuehua.wei@promab.com. (5) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. jasper.guan@promab.com. (6) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. jian.guan@promab.com. (7) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. hizkia.harto@promab.com. (8) Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. promab8807@126.com. (9) Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. yangkaihuai520@126.com. (10) Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. shuying256@163.com. (11) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. simon.li@promab.com. Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China. simon.li@promab.com. (12) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. john@promab.com. (13) ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA. vita.gol@promab.com.

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TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination

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Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naive immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription.

Author Info: (1) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (2) Department of Biosciences, Centre for

Author Info: (1) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (2) Department of Biosciences, Centre for Immune Regulation, University of Oslo, N-0316 Oslo, Norway. Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, N-0372 Oslo, Norway. Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, N-0372 Oslo, Norway. (3) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (4) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (5) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (6) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (7) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (8) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (9) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (10) MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom. (11) Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, N-0372 Oslo, Norway. (12) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (13) MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom. (14) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom. (15) Department of Biosciences, Centre for Immune Regulation, University of Oslo, N-0316 Oslo, Norway. Department of Immunology, Centre for Immune Regulation, Oslo University Hospital, N-0372 Oslo, Norway. Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, N-0372 Oslo, Norway. (16) Protein and Nucleic Acid Chemistry Division, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; lcj@mrc-lmb.cam.ac.uk.

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Chemotherapy Combines Effectively with Anti-PD-L1 Treatment and Can Augment Antitumor Responses

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Immunotherapy with checkpoint inhibitors has proved to be highly effective, with durable responses in a subset of patients. Given their encouraging clinical activity, checkpoint inhibitors are increasingly being tested in clinical trials in combination with chemotherapy. In many instances, there is little understanding of how chemotherapy might influence the quality of the immune response generated by checkpoint inhibitors. In this study, we evaluated the impact of chemotherapy alone or in combination with anti-PD-L1 in a responsive syngeneic tumor model. Although multiple classes of chemotherapy treatment reduced immune cell numbers and activity in peripheral tissues, chemotherapy did not antagonize but in many cases augmented the antitumor activity mediated by anti-PD-L1. This dichotomy between the detrimental effects in peripheral tissues and enhanced antitumor activity was largely explained by the reduced dependence on incoming cells for antitumor efficacy in already established tumors. The effects of the various chemotherapies were also agent specific, and synergy with anti-PD-L1 was achieved by different mechanisms that ultimately helped establish a new threshold for response. These results rationalize the combination of chemotherapy with immunotherapy and suggest that, despite the negative systemic effects of chemotherapy, effective combinations can be obtained through distinct mechanisms acting within the tumor.

Author Info: (1) Genentech, South San Francisco, CA 94080; and cubasr@gene.com. (2) Genentech, South San Francisco, CA 94080; and. (3) Genentech, South San Francisco, CA 94080; and

Author Info: (1) Genentech, South San Francisco, CA 94080; and cubasr@gene.com. (2) Genentech, South San Francisco, CA 94080; and. (3) Genentech, South San Francisco, CA 94080; and. (4) Genentech, South San Francisco, CA 94080; and. (5) Genentech, South San Francisco, CA 94080; and. (6) Genentech, South San Francisco, CA 94080; and. (7) Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany. (8) Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich, 82377 Penzberg, Germany. (9) Genentech, South San Francisco, CA 94080; and. (10) Genentech, South San Francisco, CA 94080; and.

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Stromal Fibroblasts Mediate Anti-PD-1 Resistance via MMP-9 and Dictate TGF-beta Inhibitor Sequencing in Melanoma

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Although anti-PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many patients exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in the development of these mechanisms of resistance to checkpoint inhibitors remains unclear. We demonstrated that pharmacological inhibition of the TGF-beta signaling pathway synergistically enhanced the efficacy of anti-CTLA-4 immunotherapy but failed to augment anti-PD-1/PD-L1 responses in an autochthonous model of BRAF(V600E) melanoma. Additional mechanistic studies revealed that TGF-beta pathway inhibition promoted the proliferative expansion of stromal fibroblasts, thereby, facilitating MMP-9-dependent cleavage of PD-L1 surface expression, leading to anti-PD-1 resistance in this model. Further work demonstrated that melanomas escaping anti-PD-1 therapy exhibited a mesenchymal phenotype associated with enhanced TGF-beta signaling activity. Delayed TGF-beta inhibitor therapy, following anti-PD-1 escape, better served to control further disease progression and was superior to a continuous combination of anti-PD-1 and TGF-beta inhibition. This work illustrates that formulating immunotherapy combination regimens to enhance the efficacy of checkpoint blockade requires an in-depth understanding of the impact of these agents on the tumor microenvironment. These data indicated that stromal fibroblast MMP-9 may desensitize tumors to anti-PD-1 and suggests that TGF-beta inhibition may generate greater immunologic efficacy when administered following the development of acquired anti-PD-1 resistance.

Author Info: (1) NIEHS/IIDL, NIH. (2) Internal Medicine/Medical Oncology, Duke University Medical Center. (3) Internal Medicine/Medical Oncology, Duke University Medical Center. (4) Medicine, Duke University Medical Center

Author Info: (1) NIEHS/IIDL, NIH. (2) Internal Medicine/Medical Oncology, Duke University Medical Center. (3) Internal Medicine/Medical Oncology, Duke University Medical Center. (4) Medicine, Duke University Medical Center. (5) Internal Medicine/Medical Oncology, Duke University Medical Center. (6) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. (7) Internal Medicine III, University Hospital Regensburg. (8) Pharmacology & Cancer Biology, Duke University Medical Center. (9) Internal Medicine/Medical Oncology and Pharmacology/Cancer Biology, Duke University Medical Center hanks004@mc.duke.edu.

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Immunomodulation Mediated by Anti-angiogenic Therapy Improves CD8 T Cell Immunity Against Experimental Glioma

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Glioblastoma (GBM) is a lethal cancer of the central nervous system with a median survival rate of 15 months with treatment. Thus, there is a critical need to develop novel therapies for GBM. Immunotherapy is emerging as a promising therapeutic strategy. However, current therapies for GBM, in particular anti-angiogenic therapies that block vascular endothelial growth factor (VEGF), may have undefined consequences on the efficacy of immunotherapy. While this treatment is primarily prescribed to reduce tumor vascularization, multiple immune cell types also express VEGF receptors, including the most potent antigen-presenting cell, the dendritic cell (DC). Therefore, we assessed the role of anti-VEGF therapy in modifying DC function. We found that VEGF blockade results in a more mature DC phenotype in the brain, as demonstrated by an increase in the expression of the co-stimulatory molecules B7-1, B7-2, and MHC II. Furthermore, we observed reduced levels of the exhaustion markers PD-1 and Tim-3 on brain-infiltrating CD8 T cells, indicating improved functionality. Thus, anti-angiogenic therapy has the potential to be used in conjunction with and enhance immunotherapy for GBM.

Author Info: (1) Department of Immunology, Mayo Clinic, Rochester, MN, United States. Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States. (2) Department

Author Info: (1) Department of Immunology, Mayo Clinic, Rochester, MN, United States. Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States. (2) Department of Immunology, Mayo Clinic, Rochester, MN, United States. Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States. (3) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (4) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (5) Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States. (6) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (7) Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States. (8) Department of Immunology, Mayo Clinic, Rochester, MN, United States. (9) Department of Immunology, Mayo Clinic, Rochester, MN, United States. Department of Neurology, Mayo Clinic, Rochester, MN, United States. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, United States.

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A cancer vaccine with dendritic cells differentiated with GM-CSF and IFNalpha and pulsed with a squaric acid treated cell lysate improves T cell priming and tumor growth control in a mouse model

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Introduction: Ovarian cancer is one of the most lethal gynecologic cancers. Relapses after remission are common, hence novel strategies are urgently needed. Our group has previously developed a vaccination approach based on dendritic cells pulsed with HOCl-oxidized tumor lysates. Here we investigate the improvement of this vaccine strategy using squaric acid treatment of cancer cells during tumor lysate preparation and by differentiating dendritic cells in the presence of GM-CSF and IFNalpha. Methods: Induction of cell death by squaric acid treatment was assessed with propidium iodide (PI) and Annexin V in ID8 tumor cells. High mobility group box 1 (HMGB1) immunogenic status was analyzed using a western blot-based method, as previously described. For immunological tests, ID8 cells expressing ovalbumin (ova-ID8) were treated with squaric acid before cell lysis. DCs prepared with the canonical GM-CSF and IL-4 differentiation cocktail or IFNalpha and GM-CSF were pulsed with tumor cell lysates and further matured in the presence of IFNgamma and LPS (4-DCs and alpha-DCs respectively). DCs were then used in co-culture assays with ova-specific T cells and IFNgamma and IL-4 secretion measured by ELISA. DC phenotypes were characterized by FACS. Finally, DCs were tested in an ovarian cancer mouse model measuring body weight and animal survival. Results: Squaric acid treatment of mouse ovarian cancer cells induced tumor cell death as well as preserve HMGB1, a crucial Damage-associated molecular pattern (DAMP) signal, in its active reduced form. Squaric acid treatment of ID8-ova cells increased IFNgamma and decreased IL-4 production from ova-specific T cells in co-culture experiments, promoting a more immunogenic cytokine secretion pattern. DCs differentiated in the presence of IFNalpha induced a considerable decrease in IL-4 production compared to canonical 4-DCs, without affecting IFNgamma release. DC phenotyping demonstrated a more mature and immunogenic phenotype for IFNalpha-differentiated DCs. Vaccination in tumor-bearing mice showed that IFNalpha-differentiated DCs pulsed with squaric acid-treated lysates were the most potent at delaying tumor growth, improving animal survival. Conclusion: We identified squaric acid as a novel immunogenic treatment of tumor cells for cancer vaccines particularly efficient in prolonging animal survival when used in combination with IFNalpha-differentiated DCs. These promising results support future efforts for the clinical translation of this approach.

Author Info: (1) Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, USA. Currently at: Cardiovascular Research Center, Icahn School of Medicine, Mount Sinai, New York, USA. (2)

Author Info: (1) Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, USA. Currently at: Cardiovascular Research Center, Icahn School of Medicine, Mount Sinai, New York, USA. (2) Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland; Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland. (3) Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, USA. Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland; Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.

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Co-inhibition of TIGIT, PD1, and Tim3 reverses dysfunction of Wilms tumor protein-1 (WT1)-specific CD8+ T lymphocytes after dendritic cell vaccination in gastric cancer

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Dendritic cell (DC) vaccines have been shown to stimulate tumor antigen-specific CD8+ T cells; however, this strategy has demonstrated variable clinical efficacy likely due to immune escape mechanisms that can induce tumor-specific CD8+ T cell dysfunction. Herein, we evaluated the functional characteristics of DC vaccine-induced CD8+ T cells with regard to immune checkpoint inhibitors in gastric cancer patients who were administered Wilms tumor protein-1 (WT1)-targeted DC vaccine. We observed the upregulation of the inhibitory molecule, TIGIT and the inhibitory T cell co-receptors PD1 and Tim3 in limiting WT1-specific CD8+ T cell growth and function in GC patients. TIGIT-expressing PD1+Tim3- CD8+ T cells were the largest subset, while TIGIT+PD1+Tim3+ was the most dysfunctional subset of WT1-specific CD8+ T cells in gastric cancer patients. Importantly, the co-inhibition of TIGIT, PD1, and Tim3 pathways enhanced the growth, proliferation, and cytokine production of WT1-specific CD8+ T cells. In conclusion, our data suggests that targeting TIGIT, PD1, and Tim3 pathways may be important in reversing immune escape in patients with advanced gastric cancer.

Author Info: (1) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (2) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (3) Department of Gastroenterology, Beijing

Author Info: (1) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (2) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (3) Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University China. (4) Key Laboratory of Digestive System Tumors, Second Hospital of Lanzhou University China. (5) Department of Oncology, Beijing Anzhen Hospital Affiliated to The Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases China. (6) Department of Biotherapy Center, Gansu Provincial Hospital China. (7) Department of Hemotology, Gansu Provincial Hospital China. (8) Department of Biochemistry and Molecular Biology, Hainan Medical College China. (9) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (10) Department of Oncology, Beijing Biohealthcare Biotechnology Co., Ltd China. (11) Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, China.

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Long-term survival of locally advanced stage III non-small cell lung cancer patients treated with chemoradiotherapy and perspectives for the treatment with immunotherapy

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Background Standard treatment for patients with inoperable locally advanced non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy (CCRT). Five-year overall survival rates range between 15 and 25%, while long term survival data are rarely reported. Patients and methods A total of 102 patients with stage III NSCLC treated between September 2005 and November 2010 with induction chemotherapy and CCRT were included in this long term survival analysis. All patients were tested for PD-L1 status and expression of PD-L1 was correlated with overall survival (OS), progression free survival (PFS) and toxicities. Results The median OS of all patients was 24.8 months (95% CI 18.7 to 31.0) with 10 year-survival rate of 11.2%. The median OS of patients with PD-L1 expression was 12.1 months (95% CI 0.1 to 26.2), while in patients with negative or unknown PD-L1 status was significantly longer, 25.2 months (95% CI 18.9 to 31.6), p = 0.005. The median PFS of all patients was 16.4 months (95% CI 13.0 to 19.9). PFS of patients with PD-L1 expression was 10.1 months (95% CI 0.1 to 20.4) and in patients with negative or unknown PD-L1 status was 17.9 months (95% CI 14.2 to 21.7), p = 0.003. Conclusions 10-year overall survival of stage III NSCLC patients after CCRT is 11.2%. PFS and OS differ with regard to PD-L1 status and are significantly shorter for patients with PD-L1 expression. New treatment with check-point inhibitors combined with RT therefore seems reasonable strategy to improve these results.

Author Info: (1) Institute of Oncology Ljubljana, Ljubljana, Slovenia. (2) Institute of Oncology Ljubljana, Ljubljana, Slovenia.

Author Info: (1) Institute of Oncology Ljubljana, Ljubljana, Slovenia. (2) Institute of Oncology Ljubljana, Ljubljana, Slovenia.

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