Journal Articles

Cytokine therapy

Treatment strategies based on cytokines, including cytokine gene therapy and immunocytokines

Canonical TGF-beta Signaling Pathway Represses Human NK Cell Metabolism

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Cytokines stimulate rapid metabolic changes in human NK cells, including increases in both glycolysis and oxidative phosphorylation pathways. However, how these are subsequently regulated is not known. In this study, we demonstrate that TGF-beta can inhibit many of these metabolic changes, including oxidative phosphorylation, glycolytic capacity, and respiratory capacity. TGF-beta also inhibited cytokine-induced expression of the transferrin nutrient receptor CD71. In contrast to a recent report on murine NK cells, TGF-beta-mediated suppression of these metabolic responses did not involve the inhibition of the metabolic regulator mTORC1. Inhibition of the canonical TGF-beta signaling pathway was able to restore almost all metabolic and functional responses that were inhibited by TGF-beta. These data suggest that pharmacological inhibition of TGF-beta could provide a metabolic advantage to NK cells that is likely to result in improved functional responses. This has important implications for NK cell-based cancer immunotherapies.

Author Info: (1) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and. (2) School of Biochemistry and Immunology, Trinity Biomedical

Author Info: (1) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and. (2) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and clair.gardiner@tcd.ie finlayd@tcd.ie. School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. (3) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; and clair.gardiner@tcd.ie finlayd@tcd.ie.

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A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma

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Background: Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/- MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rationale for combining targeted agents with immunotherapy. Methods: Patients with unresectable Stage III or IV BRAF(V600E) mutant melanoma were enrolled in a single-center prospective study (n = 6). Patients were eligible to receive two courses of HD-IL-2 and vemurafenib twice daily. The primary endpoint was progression-free survival (PFS) with secondary objectives including overall survival (OS), response rates (RR), and safety of combination therapy as compared to historical controls. Immune profiling was performed in longitudinal tissue samples, when available. Results: Overall RR was 83.3% (95% CI: 36%-99%) and 66.6% at 12 weeks. All patients eventually progressed, with three progressing on treatment and three progressing after the vemurafenib continuation phase ended. Median PFS was 35.8 weeks (95% CI: 16-57 weeks). Median OS was not reached; however, the time at which 75% of patients were still alive was 104.4 weeks. Change in circulating BRAF(V600E) levels correlated with response. Though combination therapy was associated with enhanced CD8 T cell infiltrate, an increase in regulatory T cell frequency was seen with HD-IL-2 administration, suggesting a potential limitation in this strategy. Conclusion: Combination vemurafenib and HD-IL-2 is well tolerated and associated with treatment responses. However, the HD-IL-2 induced increase in Tregs may abrogate potential synergy. Given the efficacy of regimens targeting the PD-1 pathway, strategies combining these regimens with BRAF-targeted therapy are currently underway, and the role of combination vemurafenib and HD-IL-2 is uncertain. Trial Registration: Clinical trial information: NCT01754376; https://clinicaltrials.gov/show/NCT01754376.

Author Info: (1) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (2) Department of Surgical Oncology, The University

Author Info: (1) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (2) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (3) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (4) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (5) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. (6) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (7) Department of Medicine, Harvard Medical School, Boston, MA. Department of Pathology, Massachusetts General Hospital, Boston, MA. (8) Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA. Harvard University and Massachusetts Institute of Technology, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. (9) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (10) Department of Medicine, Harvard Medical School, Boston, MA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. (11) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (12) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (13) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. (14) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (15) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Boston, MA. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.

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TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade

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Releasing the patient's immune system against their own malignancy by the use of checkpoint inhibitors is delivering promising results. However, only a subset of patients currently benefit from them. One major limitation of these therapies relates to the inability of T cells to detect or penetrate into the tumor resulting in unresponsiveness to checkpoint inhibition. Virotherapy is an attractive tool for enabling checkpoint inhibitors as viruses are naturally recognized by innate defense elements which draws the attention of the immune system. Besides their intrinsic immune stimulating properties, the adenoviruses used here are armed to express tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2). These cytokines result in immunological danger signaling and multiple appealing T-cell effects, including trafficking, activation and propagation. When these viruses were injected into B16.OVA melanoma tumors in animals concomitantly receiving programmed cell-death protein 1 (PD-1) blocking antibodies both tumor growth control (p < 0.0001) and overall survival (p < 0.01) were improved. In this set-up, the addition of adoptive cell therapy with OT-I lymphocytes did not increase efficacy further. When virus injections were initiated before antibody treatment in a prime-boost approach, 100% of tumors regressed completely and all mice survived. Viral expression of IL2 and TNFa altered the cytokine balance in the tumor microenvironment towards Th1 and increased the intratumoral proportion of CD8+ and conventional CD4+ T cells. These preclinical studies provide the rationale and schedule for a clinical trial where oncolytic adenovirus coding for TNFa and IL-2 (TILT-123) is used in melanoma patients receiving an anti-PD-1 antibody.

Author Info: (1) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (2) TILT

Author Info: (1) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (2) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (3) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (4) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (5) Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (6) Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Uusima, Finland. (7) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. (8) Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Uusima, Finland. (9) TILT Biotherapeutics Ltd, Helsinki, Uusima, Finland. Department of Oncology, Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Uusima, Finland. Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Uusima, Finland.

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M7824, a novel bifunctional anti-PD-L1/TGFbeta Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine

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Tumors evade host immune surveillance through multiple mechanisms, including the generation of a tumor microenvironment that suppresses immune effector function. Secretion of TGFbeta and upregulation of immune checkpoint programmed cell death ligand-1 (PD-L1) are two main contributors to immune evasion and tumor progression. Here, we examined the efficacy of a first-in-class bifunctional checkpoint inhibitor, the fusion protein M7824, comprising the extracellular domain of human TGFbetaRII (TGFbeta Trap) linked to the C-terminus of human anti-PD-L1 heavy chain (alphaPD-L1). We demonstrate that M7824 reduces plasma TGFbeta1, binds to PD-L1 in the tumor, and decreases TGFbeta-induced signaling in the tumor microenvironment in mice. In murine breast and colon carcinoma models, M7824 decreased tumor burden and increased overall survival as compared to targeting TGFbeta alone. M7824 treatment promoted CD8+ T cell and NK cell activation, and both of these immune populations were required for optimal M7824-mediated tumor control. M7824 was superior to TGFbeta- or alphaPD-L1-targeted therapies when in combination with a therapeutic cancer vaccine. These findings demonstrate the value of using M7824 to simultaneously target TGFbeta and PD-L1/PD-1 immunosuppressive pathways to promote anti-tumor responses and efficacy. The studies also support the potential clinical use of M7824 as a monotherapy or in combination with other immunotherapies, such as therapeutic cancer vaccines, including for patients who have progressed on alphaPD-L1/alphaPD-1 checkpoint blockade therapies.

Author Info: (1) Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Laboratory of Tumor

Author Info: (1) Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (3) Collaborative Protein Technology Resource (CPTR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (4) Collaborative Protein Technology Resource (CPTR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (5) Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (6) Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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Chronic Lymphocytic Leukemia-Derived IL-10 Suppresses Antitumor Immunity

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Chronic lymphocytic leukemia (CLL) patients progressively develop an immunosuppressive state. CLL patients have more plasma IL-10, an anti-inflammatory cytokine, than healthy controls. In vitro human CLL cells produce IL-10 in response to BCR cross-linking. We used the transgenic Emu-T cell leukemia oncogene-1 (TCL1) mouse CLL model to study the role of IL-10 in CLL associated immunosuppression. Emu-TCL mice spontaneously develop CLL because of a B cell-specific expression of the oncogene, TCL1. Emu-TCL1 mouse CLL cells constitutively produce IL-10, which is further enhanced by BCR cross-linking, CLL-derived IL-10 did not directly affect survival of murine or human CLL cells in vitro. We tested the hypothesis that the CLL-derived IL-10 has a critical role in CLL disease in part by suppressing the host immune response to the CLL cells. In IL-10R(-/-) mice, wherein the host immune cells are unresponsive to IL-10-mediated suppressive effects, there was a significant reduction in CLL cell growth compared with wild type mice. IL-10 reduced the generation of effector CD4 and CD8 T cells. We also found that activation of BCR signaling regulated the production of IL-10 by both murine and human CLL cells. We identified the transcription factor, Sp1, as a novel regulator of IL-10 production by CLL cells and that it is regulated by BCR signaling via the Syk/MAPK pathway. Our results suggest that incorporation of IL-10 blocking agents may enhance current therapeutic regimens for CLL by potentiating host antitumor immune response.

Author Info: (1) Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536. Markey Cancer Center, University of Kentucky, Lexington, KY 40536. (2) Department

Author Info: (1) Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536. Markey Cancer Center, University of Kentucky, Lexington, KY 40536. (2) Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536. Markey Cancer Center, University of Kentucky, Lexington, KY 40536. (3) Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536. Markey Cancer Center, University of Kentucky, Lexington, KY 40536. (4) Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536. Markey Cancer Center, University of Kentucky, Lexington, KY 40536. Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536. (5) Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536. Markey Cancer Center, University of Kentucky, Lexington, KY 40536. (6) Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536. Markey Cancer Center, University of Kentucky, Lexington, KY 40536. Division of Hematology, Blood, and Marrow Transplantation, University of Kentucky, Lexington, KY 40536. (7) Markey Cancer Center, University of Kentucky, Lexington, KY 40536. Division of Hematology, Blood, and Marrow Transplantation, University of Kentucky, Lexington, KY 40536. (8) Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536. Markey Cancer Center, University of Kentucky, Lexington, KY 40536. Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536. (9) Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; and. Department of Internal Medicine, The Ohio State University, Columbus, OH 43210. (10) Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536; bondada@email.uky.edu. Markey Cancer Center, University of Kentucky, Lexington, KY 40536.

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IL-21 Increases the Reactivity of Allogeneic Human Vgamma9Vdelta2 T Cells Against Primary Glioblastoma Tumors

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Glioblastoma multiforme (GBM) remains the most frequent and deadliest primary brain tumor in adults despite aggressive treatments, because of the persistence of infiltrative and resistant tumor cells. Nonalloreactive human Vgamma9Vdelta2 T lymphocytes, the major peripheral gammadelta T-cell subset in adults, represent attractive effectors for designing immunotherapeutic strategies to track and eliminate brain tumor cells, with limited side effects. We analyzed the effects of ex vivo sensitizations of Vgamma9Vdelta2 T cells by IL-21, a modulating cytokine, on their cytolytic reactivity. We first showed that primary human GBM-1 cells were naturally eliminated by allogeneic Vgamma9Vdelta2 T lymphocytes, through a perforin/granzyme-mediated cytotoxicity. IL-21 increased both intracellular granzyme B levels and cytotoxicity of allogeneic human Vgamma9Vdelta2 T lymphocytes in vitro. Importantly, IL-21-enhanced cytotoxicity was rapid, which supports the development of sensitization(s) of gammadelta T lymphocytes before adoptive transfer, a process that avoids any deleterious effect associated with direct administrations of IL-21. Finally, we showed, for the first time, that IL-21-sensitized allogeneic Vgamma9Vdelta2 T cells significantly eliminated GBM tumor cells that developed in the brain after orthotopic administrations in vivo. Altogether our observations pave the way for novel efficient stereotaxic immunotherapies in GBM patients by using IL-21-sensitized allogeneic human Vgamma9Vdelta2 T cells.

Author Info: (1) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (2) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO

Author Info: (1) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (2) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (3) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". Hotel Dieu, Hopital de Nantes, Nantes, France. (4) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (5) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (6) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology". (7) CRCINA, INSERM, CNRS, Universite d'Angers, Universite de Nantes. LabEx IGO "Immunotherapy, Graft, Oncology".

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Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance

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Antineoplastic platinum agents are used in first-line treatment of ovarian cancer, but treatment failure frequently results from platinum drug resistance. Emerging observations suggest a role of reactive oxygen species (ROS) in the resistance of cancer drugs including platinum drugs. However, the molecular link between ROS and cellular survival pathway is poorly understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we show that in platinum-resistant ovarian cancer elevated ROS levels sustain high level of IL-11 by stimulating FRA1-mediated IL-11 expression and increased IL-11 causes resistance to platinum drugs by constitutively activating JAK2-STAT5 via an autocrine mechanism. Inhibition of JAK2 by LY2784544 or IL-11 by anti-IL-11 antibody overcomes the platinum resistance in vitro or in vivo. Significantly, clinic studies also confirm the activated IL-11-JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis. These findings not only identify a novel ROS-IL-11-JAK2-mediated platinum resistance mechanism but also provide a new strategy for using LY2784544- or IL-11-mediated immunotherapy to treat platinum-resistant ovarian cancer.

Author Info: (1) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. Department of Colorectal Surgery

Author Info: (1) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. (2) National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA. (3) Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. (4) Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA. (5) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. (6) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. (7) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. (8) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. (9) National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA. (10) Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. (11) National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA. (12) National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA. (13) Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. (14) Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. (15) Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. (16) GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. Department of Physics, The George Washington University Columbian College of Arts & Sciences, Washington, DC, 20052, USA. (17) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. (18) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. (19) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. (20) Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. (21) Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. (22) Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. (23) Department of Pathology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. (24) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. (25) Department of Oncology, the Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China. (26) GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. Department of Anatomy and Regenerative Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. (27) Department of Physics, The George Washington University Columbian College of Arts & Sciences, Washington, DC, 20052, USA. (28) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. (29) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. (30) Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. dwchan@hku.hk. (31) National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA. wzheng@mail.nih.gov. (32) Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA. wz6812@gwu.edu. GW Cancer Centre, The George Washington University, Washington, DC, 20052, USA. wz6812@gwu.edu.

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Role of IL-23 signaling in the progression of premalignant oral lesions to cancer

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Mice bearing carcinogen-induced premalignant oral lesions were previously shown to have a pro-inflammatory phenotype, which is replaced with an immune inhibitory phenotype as lesions progress to cancer. Since Th17 cells are prominent at the premalignant lesion state and their levels are supported by IL-23, studies used mice that were IL-23 receptor deficient (IL-23R KO) to determine the requirement for IL-23 signaling in the immunological and clinical status of mice with premalignant oral lesions. The results showed a dependence on IL-23 signaling for the pro-inflammatory state of mice with oral lesions as levels of IL-2, IFN-gamma, IL-6, IL-17 and TNF-alpha were elevated in wildtype mice with premalignant oral lesions, but not in IL-23R KO mice. In contrast, as lesions progressed to cancer, the pro-inflammatory phenotype subsided and was replaced with the inhibitory mediator IL-10 and with Treg cells in wildtype mice, although not in IL-23R KO mice. Clinically, early progression of premalignant oral lesions to cancer was enhanced in IL-23R KO mice compared to progression in wildtype mice. These results show the importance of IL-23 signaling in both the pro-inflammatory phenotype characteristic of premalignant oral lesions and the inhibitory phenotype as lesions progress to cancer.

Author Info: (1) Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC, United States of America. (2) Department of Microbiology and Immunology, Medical University of South

Author Info: (1) Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC, United States of America. (2) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States of America. (3) Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC, United States of America. Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, United States of America.

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Autoantibodies to Chemokines and Cytokines Participate in the Regulation of Cancer and Autoimmunity

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We have previously shown that predominant expression of key inflammatory cytokines and chemokines at autoimmune sites or tumor sites induces loss of B cells tolerance, resulting in autoantibody production against the dominant cytokine/chemokine that is largely expressed at these sites. These autoantibodies are high-affinity neutralizing antibodies. Based on animal models studies, we suggested that they participate in the regulation of cancer and autoimmunity, albeit at the level of their production cannot entirely prevent the development and progression of these diseases. We have, therefore, named this selective breakdown of tolerance as "Beneficial Autoimmunity." Despite its beneficial outcome, this process is likely to be stochastic and not directed by a deterministic mechanism, and is likely to be associated with the dominant expression of these inflammatory mediators at sites that are partially immune privileged. A recent study conducted on autoimmune regulator-deficient patients reported that in human this type of breakdown of B cell tolerance is T cell dependent. This explains, in part, why the response is highly restricted, and includes high-affinity antibodies. The current mini-review explores this subject from different complementary perspectives. It also discusses three optional translational aspects: amplification of autoantibody production as a therapeutic approach, development of autoantibody based diagnostic tools, and the use of B cells from donors that produce these autoantibodies for the development of high-affinity human monoclonal antibodies.

Author Info: (1) Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Author Info: (1) Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

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ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial

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BACKGROUND: Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rbetagamma pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. METHODS: In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged >/=18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 mug/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS: Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 mug/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION: ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC. FUNDING: Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.

Author Info: (1) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (2) Cleveland Clinic, Cleveland

Author Info: (1) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (2) Cleveland Clinic, Cleveland, OH, USA. (3) Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA. (4) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (5) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (6) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (7) Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA. (8) Earle A Chiles Research Institute, Portland, OR, USA. (9) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (10) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (11) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (12) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (13) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (14) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (15) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (16) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (17) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (18) Adaptive Biotechnologies, Seattle, WA, USA. (19) Adaptive Biotechnologies, Seattle, WA, USA. (20) Adaptive Biotechnologies, Seattle, WA, USA. (21) Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland. (22) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. (23) Earle A Chiles Research Institute, Portland, OR, USA. (24) Altor BioScience, Miramar, FL, USA. (25) Altor BioScience, Miramar, FL, USA. (26) Altor BioScience, Miramar, FL, USA. (27) Altor BioScience, Miramar, FL, USA. (28) Altor BioScience, Miramar, FL, USA. (29) Department of Medicine, Division of Hematology and Oncology, and Department of Surgery Medical University of South Carolina, Charleston, SC, USA. Electronic address: markrubinstein@musc.edu.

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