Journal Articles

Immune cell biology

Biology of T cells, professional antigen presenting cells and other immune cell subsets; antigen processing and presentation

Autologous lymphocyte infusion supports tumor antigen vaccine-induced immunity in autologous stem cell transplant for multiple myeloma

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Autologous stem cell transplant (autoSCT), the standard consolidation therapy for multiple myeloma, improves disease-free survival but is not curative. This could be an ideal setting for immunologic therapy. However, the immune milieu is impaired after autoSCT. We hypothesized that autologous lymphocyte infusion would restore immune competence, allowing immunotherapies such as cancer vaccines to elicit tumor antigen-specific immunity in the setting of autoSCT. In this pilot study (NCT01380145), we investigated safety, immunologic, and clinical outcomes of autologous lymphocyte infusion combined with peri-autoSCT immunotherapy with recombinant MAGE-A3 (a multiple myeloma-associated antigen) and adjuvant. Thirteen multiple myeloma patients undergoing autoSCT were enrolled. Autologous lymphocyte infusion and MAGE vaccination were well tolerated. Combination immunotherapy resulted in high-titer humoral immunity and robust, antigen-specific CD4+ T-cell responses in all subjects, and the responses persisted at least one year post-autoSCT. CD4+ T cells were polyfunctional and Th1-biased. CD8+ T-cell responses were elicited in 3/13 subjects. These cells recognized naturally processed MAGE-A3 antigen. Median progression-free survival was 27 months, and median overall survival was not reached, suggesting no differences from standard-of-care. In 4/8 subjects tested, MAGE-A protein expression was not detected by immunohistochemistry in multiple myeloma cells at relapse, suggesting therapy-induced immunologic selection against antigen-expressing clones. These results demonstrated that autologous lymphocyte infusion augmentation of autoSCT confers a favorable milieu for immunotherapies such as tumor vaccines. This strategy does not require ex vivo manipulation of autologous lymphocyte products and is an applicable platform for further investigation into combination immunotherapies to treat multiple myeloma.

Author Info: (1) Medicine, Abramson Cancer Center, University of Pennsylvania. (2) Department of Medicine, Memorial Sloan Kettering Cancer Center. (3) Hematology/Oncology, Weill Cornell Medicine. (4) Tisch Cancer

Author Info: (1) Medicine, Abramson Cancer Center, University of Pennsylvania. (2) Department of Medicine, Memorial Sloan Kettering Cancer Center. (3) Hematology/Oncology, Weill Cornell Medicine. (4) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai. (5) Department of Pathology, Memorial Sloan Kettering Cancer Center. (6) Department of Medicine, Memorial Sloan Kettering Cancer Center. (7) Human Immune Monitoring Core, Mount Sinai School of Medicine. (8) Multiple Myeloma Program, Tisch Cancer Insititute, Icahn School of Medicine at Mount Sinai. (9) Multiple Myeloma Program, Tisch Cancer Insititute, Icahn School of Medicine at Mount Sinai. (10) Multiple Myeloma Program, Tisch Cancer Insititute, Icahn School of Medicine at Mount Sinai. (11) Oncological Sciences, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai. (12) Clinical Trial Operations, Ludwig Institute for Cancer Research. (13) Administration, Ludwig Cancer Research. (14) Protocol Support Laboratory, Fox Chase Cancer Center. (15) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai. (16) Multiple Myeloma Program, Tisch Cancer Insititute, Icahn School of Medicine at Mount Sinai hearn.jay.cho@mssm.edu.

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Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients

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Background: Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we designed a phase I/II study to test safety and immunogenicity of the IMA950 multipeptide vaccine adjuvanted with poly-ICLC in HLA-A2 + glioma patients. Methods: Adult patients with newly diagnosed glioblastoma (n=16) and grade III astrocytoma (n=3) were treated with radiochemotherapy followed by IMA950/poly-ICLC vaccination. The first 6 patients received IMA950 (9 MHC class I and 2 MHC class II peptides) i.d. and poly-ICLC i.m. After protocol amendment, IMA950 and poly-ICLC were mixed and injected s.c. (n=7) or i.m. (n=6). Primary endpoints were safety and immunogenicity. Secondary endpoints were overall survival, progression-free survival at 6 and 9 months, and vaccine-specific peripheral CD4 and CD8 T cell responses. Results: The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery. For the first 6 patients, vaccine-induced CD8 T cell responses were restricted to a single peptide and CD4 responses were absent. After optimization of vaccine formulation, we observed multipeptide CD8 and sustained Th1 CD4 T cell responses. For the entire cohort, CD8 T cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients. Conclusion: We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for glioma patients. Trial registration: Clinicaltrials.gov NCT01920191.

Author Info: (1) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (2) Laboratory of Tumor immunology and

Author Info: (1) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (2) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (3) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (4) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (5) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (6) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (7) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (8) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (9) Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland. (10) Neuropathology Division, Department of Pathology, Geneva University Hospital, Geneva, Switzerland. (11) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (12) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (13) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (14) Neurosurgery Division, Department of Neurosciences, Geneva University Hospital, Geneva, Switzerland. (15) Neurosurgery Division, Department of Neurosciences, Geneva University Hospital, Geneva, Switzerland. (16) Neuropathology Division, Department of Pathology, Geneva University Hospital, Geneva, Switzerland. (17) Neuropathology Division, Department of Pathology, Geneva University Hospital, Geneva, Switzerland. (18) Department of Imaging and Medical information Sciences, Neuroradiology Division, Geneva University Hospital, Geneva, Switzerland. (19) Laboratory of Tumor immunology, Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, & Division of Oncology, HUG, Geneva, Switzerland. (20) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. (21) Department of Oncology, Clinical Research Unit, Dr Dubois Ferriere Dinu Lipatti Research Foundation, Geneva University Hospital, Geneva, Switzerland. Laboratory of Tumor immunology and Department of Oncology, Geneva University Hospital, Geneva, Switzerland. Translational research center for oncohaematology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland.

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An immunoproteomic approach to characterize the CAR interactome and signalosome

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Adoptive transfer of T cells that express a chimeric antigen receptor (CAR) is an approved immunotherapy that may be curative for some hematological cancers. To better understand the therapeutic mechanism of action, we systematically analyzed CAR signaling in human primary T cells by mass spectrometry. When we compared the interactomes and the signaling pathways activated by distinct CAR-T cells that shared the same antigen-binding domain but differed in their intracellular domains and their in vivo antitumor efficacy, we found that only second-generation CARs induced the expression of a constitutively phosphorylated form of CD3zeta that resembled the endogenous species. This phenomenon was independent of the choice of costimulatory domains, or the hinge/transmembrane region. Rather, it was dependent on the size of the intracellular domains. Moreover, the second-generation design was also associated with stronger phosphorylation of downstream secondary messengers, as evidenced by global phosphoproteome analysis. These results suggest that second-generation CARs can activate additional sources of CD3zeta signaling, and this may contribute to more intense signaling and superior antitumor efficacy that they display compared to third-generation CARs. Moreover, our results provide a deeper understanding of how CARs interact physically and/or functionally with endogenous T cell molecules, which will inform the development of novel optimized immune receptors.

Author Info: (1) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (2) Department of Immunology, H. Lee Moffitt Cancer Center

Author Info: (1) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (2) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (3) Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620, USA. (4) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (5) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL 33620, USA. (6) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (7) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (8) Proteomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (9) Proteomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (10) Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (11) Molecular Genomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (12) Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (13) Proteomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (14) Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (15) Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. daniel.abatedaga@moffitt.org. Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.

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Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma

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Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival(1,2). Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.

Author Info: (1) Department of Pathology, Yale School of Medicine, New Haven, CT, USA. (2) Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. Centro de Investigacion

Author Info: (1) Department of Pathology, Yale School of Medicine, New Haven, CT, USA. (2) Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. Centro de Investigacion Biomedica en Red de Oncologia (CIBERONC), Madrid, Spain. Instituto de Investigacion Sanitaria de Navarra (IDISNA), Pamplona, Spain. (3) Department of Neurosurgery, Clinica Universidad de Navarra, Pamplona, Spain. Department of Immunology, Clinica Universidad de Navarra, Pamplona, Spain. (4) Department of Pathology, Clinica Universidad de Navarra, Pamplona, Spain. (5) Department of Pathology, Yale School of Medicine, New Haven, CT, USA. (6) Department of Pathology, Clinica Universidad de Navarra, Pamplona, Spain. (7) Department of Immunology, Clinica Universidad de Navarra, Pamplona, Spain. (8) Department of Pathology, Clinica Universidad de Navarra, Pamplona, Spain. (9) Department of Immunology, Clinica Universidad de Navarra, Pamplona, Spain. (10) Department of Neurosurgery, Clinica Universidad de Navarra, Pamplona, Spain. (11) Centro de Investigacion Medica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain. (12) Department of Pathology, Yale School of Medicine, New Haven, CT, USA. (13) Department of Genetics, Yale School of Medicine, New Haven, CT, USA. (14) Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. (15) Department of Pharmacy, Clinica Universidad de Navarra, Pamplona, Spain. (16) Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. (17) Department of Neurology, Clinica Universidad de Navarra, Pamplona, Spain. (18) Department of Pathology, Yale School of Medicine, New Haven, CT, USA. Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. (19) Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain. Centro de Investigacion Biomedica en Red de Oncologia (CIBERONC), Madrid, Spain. Instituto de Investigacion Sanitaria de Navarra (IDISNA), Pamplona, Spain. (20) Centro de Investigacion Biomedica en Red de Oncologia (CIBERONC), Madrid, Spain. imelero@unav.es. Instituto de Investigacion Sanitaria de Navarra (IDISNA), Pamplona, Spain. imelero@unav.es. Department of Neurosurgery, Clinica Universidad de Navarra, Pamplona, Spain. imelero@unav.es. Department of Immunology, Clinica Universidad de Navarra, Pamplona, Spain. imelero@unav.es.

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Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma

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Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.

Author Info: (1) Department of Systems Biology, Columbia University, New York, NY, USA. Department of Biomedical Informatics, Columbia University, New York, NY, USA. (2) Department of Systems

Author Info: (1) Department of Systems Biology, Columbia University, New York, NY, USA. Department of Biomedical Informatics, Columbia University, New York, NY, USA. (2) Department of Systems Biology, Columbia University, New York, NY, USA. (3) Department of Pediatrics, Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, NY, USA. (4) Department of Pediatrics, Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, NY, USA. (5) Department of Systems Biology, Columbia University, New York, NY, USA. Department of Biomedical Informatics, Columbia University, New York, NY, USA. (6) Department of Systems Biology, Columbia University, New York, NY, USA. Department of Biomedical Informatics, Columbia University, New York, NY, USA. (7) Department of Pediatrics, Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, NY, USA. (8) Department of Pediatrics, Pediatric Hematology/Oncology/SCT, Columbia University Irving Medical Center, New York, NY, USA. (9) Department of Neurosurgery, Columbia University, New York, NY, USA. (10) Department of Neurosurgery, Columbia University, New York, NY, USA. (11) Department of Systems Biology, Columbia University, New York, NY, USA. (12) Department of Systems Biology, Columbia University, New York, NY, USA. (13) Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (14) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (15) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (16) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (17) Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (18) Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. (19) Department of Neurological Surgery, Oregon Health & Sciences University, Portland, OR, USA. (20) Department of Biomedical Informatics, Columbia University, New York, NY, USA. (21) Department of Pathology and Cell Biology, Columbia University, New York, NY, USA. (22) Department of Neurosurgery, Columbia University, New York, NY, USA. (23) Department of Medicine, Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA. (24) Department of Biomedical Informatics, Columbia University, New York, NY, USA. (25) Department of Neurology, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. fi2146@cumc.columbia.edu. (26) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Adam.Sonabend@nm.org. (27) Department of Systems Biology, Columbia University, New York, NY, USA. rr2579@cumc.columbia.edu. Department of Biomedical Informatics, Columbia University, New York, NY, USA. rr2579@cumc.columbia.edu.

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Landscape of B cell immunity and related immune evasion in human cancers

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Tumor-infiltrating B cells are an important component in the microenvironment but have unclear anti-tumor effects. We enhanced our previous computational algorithm TRUST to extract the B cell immunoglobulin hypervariable regions from bulk tumor RNA-sequencing data. TRUST assembled more than 30 million complementarity-determining region 3 sequences of the B cell heavy chain (IgH) from The Cancer Genome Atlas. Widespread B cell clonal expansions and immunoglobulin subclass switch events were observed in diverse human cancers. Prevalent somatic copy number alterations in the MICA and MICB genes related to antibody-dependent cell-mediated cytotoxicity were identified in tumors with elevated B cell activity. The IgG3-1 subclass switch interacts with B cell-receptor affinity maturation and defects in the antibody-dependent cell-mediated cytotoxicity pathway. Comprehensive pancancer analyses of tumor-infiltrating B cell-receptor repertoires identified novel tumor immune evasion mechanisms through genetic alterations. The IgH sequences identified here are potentially useful resources for future development of immunotherapies.

Author Info: (1) Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA. (2) Center for Computational Biology, Beijing

Author Info: (1) Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA. (2) Center for Computational Biology, Beijing Institute of Basic Medical Sciences, Beijing, China. (3) Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA. Shanghai Key Laboratory of Tuberculosis, Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. (4) Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA. Shanghai Key Laboratory of Tuberculosis, Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. (5) State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. (6) Department of Mathematics, Shanghai Normal University, Shanghai, China. (7) Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA. Shanghai Key Laboratory of Tuberculosis, Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. (8) Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA. (9) Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA. (10) Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA. Shanghai Key Laboratory of Tuberculosis, Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. (11) Center for Computational Biology, Beijing Institute of Basic Medical Sciences, Beijing, China. (12) Shanghai Key Laboratory of Tuberculosis, Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. (13) Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. (14) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (15) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. (16) Shanghai Key Laboratory of Tuberculosis, Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. (17) Shanghai Key Laboratory of Tuberculosis, Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. (18) Department of Statistics, Harvard University, Cambridge, MA, USA. jliu@stat.harvard.edu. (19) Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA. bo.li@utsouthwestern.edu. (20) Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA. xsliu@jimmy.harvard.edu. Shanghai Key Laboratory of Tuberculosis, Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. xsliu@jimmy.harvard.edu. Department of Statistics, Harvard University, Cambridge, MA, USA. xsliu@jimmy.harvard.edu.

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IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma

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Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF secreting allogenic pancreatic tumor cell vaccine (GVAX), may prime the tumor microenvironment by inducing intratumoral T-cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2, 3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates. IDO1 expression plays a role in regulating the polarization of Th1, Th17, and possibly T-regulatory cells in PDAC tumors. IDO1 inhibitor enhanced anti-tumor efficacy of GVAX in a murine model of PDACs. The combination of vaccine and IDO1 inhibitor enhanced intratumoral T-cell infiltration and function, but adding anti-PD-L1 antibody to the combination did not offer further synergy and in fact may have a negative interaction decreasing the number of intratumoral effector T-cells. Additionally, IDO1 inhibitor in the presence of vaccine therapy, did not significantly modulate intratumoral myeloid derived suppressor cells quantitatively, but diminished their suppressive effect on CD8+ proliferation. Our study thus supports the combination of IDO1 inhibitor and vaccine therapy, however, does not support the combination of IDO1 inhibitor and anti-PD-1/PD-L1 antibody for T cell-inflamed tumors such as PDACs treated with vaccine therapy.

Author Info: (1) (2) (3) (4) (5) (6) (7)

Author Info: (1) (2) (3) (4) (5) (6) (7)

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Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy

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Cancer immunotherapies provide survival benefits in responding patients, but many patients fail to respond. Identifying the biology of treatment response and resistance are a priority to optimize drug selection and improve patient outcomes. We performed transcriptomic and immune profiling on 158 tumor biopsies from melanoma patients treated with anti-PD-1 monotherapy (n = 63) or combined anti-PD-1 and anti-CTLA-4 (n = 57). These data identified activated T cell signatures and T cell populations in responders to both treatments. Further mass cytometry analysis identified an EOMES(+)CD69(+)CD45RO(+) effector memory T cell phenotype that was significantly more abundant in responders to combined immunotherapy compared with non-responders (n = 18). The gene expression profile of this population was associated with longer progression-free survival in patients treated with single agent and greater tumor shrinkage in both treatments.

Author Info: (1) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. (2) Melanoma

Author Info: (1) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. (2) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. (3) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia; Department of Medical Oncology, Mater Hospital, North Sydney, NSW 2060, Australia. (4) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia. (5) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia. (6) Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Centenary Institute, The University of Sydney, Sydney, NSW 2050, Australia. (7) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia. (8) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia. (9) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia. (10) Oncology Biomarker Development, Genentech Inc, South San Francisco, CA 94080, USA. (11) Oncology Biomarker Development, Genentech Inc, South San Francisco, CA 94080, USA. (12) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia. (13) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, NSW 2145, Australia. (14) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia; Department of Medical Oncology, Mater Hospital, North Sydney, NSW 2060, Australia. (15) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia. (16) Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Centenary Institute, The University of Sydney, Sydney, NSW 2050, Australia. (17) Ramaciotti Facility for Human Systems Biology, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Discipline of Pathology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia. (18) Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Centenary Institute, The University of Sydney, Sydney, NSW 2050, Australia. (19) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia. (20) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia. (21) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. (22) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. (23) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia. (24) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia; Department of Medical Oncology, Mater Hospital, North Sydney, NSW 2060, Australia. (25) Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: james.wilmott@melanoma.org.au.

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Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells

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The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.

Author Info: (1) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. (2) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill

Author Info: (1) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. (2) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. (3) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. (4) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. (5) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. (6) Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (7) Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA. (8) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. (9) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA. (10) Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. (11) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. (12) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. (13) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. (14) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. (15) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. (16) Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (17) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA. (18) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Surgery, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA. (19) Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA. (20) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA. (21) Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. (22) Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: gdotti@med.unc.edu.

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A T-cell-engaging B7-H4/CD3 bispecific Fab-scFv antibody targets human breast cancer

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PURPOSE: The B7 homolog 4 (B7-H4, VTCN1) is an immune checkpoint molecule that negatively regulates immune responses and is known to be overexpressed in many human cancers. Previously, we generated a mouse anti-human B7-H4 monoclonal antibody that did not have a significant antitumor effect in vivo probably because of molecule instability. In this study, we designed a B7-H4/CD3 bispecific antibody (BsAb) and investigated its antitumor activity in vitro and in vivo using a humanized mouse model. EXPERIMENTAL DESIGN: Complementary DNAs of the antibody-binding fragment (Fab)-single-chain variable fragment (scFv) and scFv-scFv of the anti-B7-H4/CD3 BsAb were synthesized, and the BsAb antibodies were produced in HEK293 cells. The anti-tumor activity against human breast cancer cells by human peripheral blood mononuclear cells (hPBMC) with BsAb was measured by lactate dehydrogenase (LDH) release in vitro, and in vivo using hPBMC transplanted major histocompatibility (MHC) class I and class II-deficient NOG mice. RESULTS: hPBMCs with anti-B7-H4/CD3 BsAbs successfully lysed the human breast cancer cell line MDA-MB-468 (EC50: 0.2 ng/ml) and other B7-H4-positive cell lines in vitro When BsAb was injected in a humanized mouse model, there was an immediate and strong antitumor activity against MDA-MB-468, HCC-1954 and HCC-1569 tumors and CD8(+) and granzyme B(+) CTL infiltration into the tumor, and there were no adverse effects after long-term observation. CD8(+) T cell depletion by an anti-CD8 antibody mostly reduced the antitumor effect of BsAb in vivo Conclusions:An anti-B7-H4/CD3 bispecific antibody may be a good therapeutic tool for patients with B7-H4-positive breast cancers.

Author Info: (1) Immunotherapy Division, Shizuoka Cancer Center Research Institute. (2) Immunotherapy Division, Shizuoka Cancer Center Research Institute. (3) Immunotherapy Division, Shizuoka Cancer Center Research Institute. (4)

Author Info: (1) Immunotherapy Division, Shizuoka Cancer Center Research Institute. (2) Immunotherapy Division, Shizuoka Cancer Center Research Institute. (3) Immunotherapy Division, Shizuoka Cancer Center Research Institute. (4) Immunotherapy Division, Shizuoka Cancer Center Research Institute. (5) Medical Genetics Division, Shizuoka Cancer Center Institute. (6) Pathology, Fukushima Medical University. (7) Division of Neurosurgery, Shizuoka Cancer Center Hospital. (8) Division of Neurosurgery, Shizuoka Cancer Center Hospital. (9) Neurosurgery, Shizuoka Cancer Center. (10) Experimental Animal Facility, Shizuoka Cancer Center Research Institute. (11) Office of the President, Shizuoka Cancer Center. (12) Immunotherapy Division, Shizuoka Cancer Center Research Institute y.akiyama@scchr.jp.

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