Journal Articles

Recent Articles

Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia (T-ALL)

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As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-ALL, however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multi-agent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of non-hematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human IgG1kappa monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma (MM). We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.

Author Info: (1) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University

Author Info: (1) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (2) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (3) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (4) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (5) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (6) Laura and Isaac Perlmutter Cancer Center at NYU Langone, New York University, New York, NY, United States. (7) Janssen Biotech, Horsham, PA, United States. (8) University of Florida, Gainesville, FL, United States. (9) University of Florida, Gainesville, FL, United States. (10) Carilion Children's Clinic, Roanoke, VA, United States. (11) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (12) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (13) Baylor College of Medicine Dan L Duncan Comprehensive Cancer Center, Houston, TX, United States. (14) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (15) Division of Hematology/Oncology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, United States. (16) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (17) Department of Pediatrics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States. (18) Children's Minnesota Cancer and Blood Disorders, Minneapolis, MN, United States. (19) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States. (20) Division of Hematology/Oncology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, United States. (21) Seattle Children's Hospital, Seattle, WA, United States. (22) Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Penn., Philadelphia, PA, United States; teacheyd@email.chop.edu.

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Soluble SLAMF6 receptor induces strong CD8+ T cell effector function and improves anti-melanoma activity in vivo

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SLAMF6, a member of the SLAM (signaling lymphocyte activation molecules) family, is a homotypic-binding immune receptor expressed on NK, T, and B lymphocytes. Phosphorylation variance between T-cell subclones prompted us to explore its role in anti-melanoma immunity. Using a 203-amino acid sequence of the human SLAMF6 (seSLAMF6) ectodomain, we found that seSLAMF6 reduced activation-induced cell death and had an anti-apoptotic effect on tumor infiltrating lymphocytes. CD8+ T cells costimulated with seSLAMF6 secreted more interferon gamma and displayed augmented cytolytic activity. The systemic administration of seSLAMF6 to mice sustained adoptively transferred transgenic CD8+ T cells in comparable numbers to high doses of interleukin-2. In a therapeutic model, lymphocytes activated by seSLAMF6 delayed tumor growth, and when further supported in vivo with seSLAMF6, induced complete tumor clearance. The ectodomain expedites the loss of phosphorylation on SLAMF6 that occurs in response to T-cell receptor triggering. Our findings suggest that seSLAMF6 is a costimulator that could be used in melanoma immunotherapy.

Author Info: (1) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital galiteis@gmail.com. (2) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (3) Sharrett Institute of Oncology, Hadassah

Author Info: (1) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital galiteis@gmail.com. (2) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (3) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (4) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (5) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (6) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (7) Weizmann Institute of Science. (8) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (9) Compugen Ltd. (10) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (11) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital. (12) Sharrett Institute of Oncology, Hadassah Hebrew University Hospital.

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High macrophage PD-L1 expression not responsible for T cell suppression

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Tumors are often comprised of microenvironments (TMEs) with a high proportion of cells and molecules that regulate immunity. Peritoneal cavity (PerC) cell culture reproduces key features of TMEs as lymphocyte proliferation is suppressed by PerC macrophages (Mvarphis). We monitored the expression of T cell stimulatory (Class II MHC, B7) and inhibitory (PD-L1) molecules by PerC APCs before and after culture and report here that IFNgamma-driven PD-L1 expression increased markedly on PerC Mvarphis after TCR ligation, even more so than seen with direct APC activation by LPS. Considering the high APC composition of and pronounced PD-L1 expression by PerC cells, it was surprising that blocking PD-1/PD-L1 interaction by mAb neutralization or genetic ablation did not relieve suppression. This result parallels TME challenges observed in the clinic and validates the need for further study of this culture model to inform strategies to promote anti-tumor immunity.

Author Info: (1) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (2) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (3) Department of Biology, Rider

Author Info: (1) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (2) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (3) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (4) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (5) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (6) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. (7) Department of Biology, Rider University, Lawrenceville, NJ, 08648, USA. Electronic address: riggs@rider.edu.

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NF-kappaB and the Transcriptional Control of Inflammation

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The NF-kappaB transcription factor was discovered 30 years ago and has since emerged as the master regulator of inflammation and immune homeostasis. It achieves this status by means of the large number of important pro- and antiinflammatory factors under its transcriptional control. NF-kappaB has a central role in inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and autoimmunity, as well as diseases comprising a significant inflammatory component such as cancer and atherosclerosis. Here, we provide an overview of the studies that form the basis of our understanding of the role of NF-kappaB subunits and their regulators in controlling inflammation. We also describe the emerging importance of posttranslational modifications of NF-kappaB in the regulation of inflammation, and highlight the future challenges faced by researchers who aim to target NF-kappaB transcriptional activity for therapeutic benefit in treating chronic inflammatory diseases.

Author Info: (1) Rheumatoid Arthritis Pathogenesis Centre of Excellence, Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United Kingdom. (2) Centre for

Author Info: (1) Rheumatoid Arthritis Pathogenesis Centre of Excellence, Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United Kingdom. (2) Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United Kingdom. Electronic address: ruaidhri.carmody@glasgow.ac.uk.

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Immune Consequences of in vitro Infection of Human Peripheral Blood Leukocytes with Vesicular Stomatitis Virus

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BACKGROUND: Oncolytic vesicular stomatitis virus (VSV) can be delivered intravenously to target primary and metastatic lesions, but the interaction between human peripheral blood leukocytes (PBLs) and VSV remains poorly understood. Our study aimed to assess the overall immunological consequences of ex vivo infection of PBLs with VSV. METHODS: Phenotypic analysis of lymphocyte subsets and apoptosis were evaluated with flow cytometry. Caspase 3/7 activity was detected by luminescence assay. Virus release was evaluated in a murine cell line (L929). Gene expression and cytokine/chemokine secretion were assessed by real-time PCR and multiplex assay, respectively. RESULTS: Ex vivo infection of PBLs with VSV elicited upregulated expression of RIG-I, MDA-5, tetherin, IFITM3, and MxA. VSV infection triggered rapid differentiation of blood monocytes into immature dendritic cells as well as their apoptosis, which depended on caspase 3/7 activation. Monocyte differentiation required infectious VSV, but loss of CD14+ cells was also associated with the presence of a cytokine/chemokine milieu produced in response to VSV infection. CONCLUSIONS: Systemic delivery is a major goal in the field of oncolytic viruses. Our results shed further light on immune mechanisms in response to VSV infection and the underlying VSV-PBL interactions bringing hope for improved cancer immunotherapies, particularly those based on intravenous delivery of oncolytic VSV.

Author Info: (1) Laboratory of Virology, Institute of Immunology and Experimental Therapy (IIET), Polish Academy of Sciences, Wroclaw, Poland. (2) (3) (4) (5) (6) (7)

Author Info: (1) Laboratory of Virology, Institute of Immunology and Experimental Therapy (IIET), Polish Academy of Sciences, Wroclaw, Poland. (2) (3) (4) (5) (6) (7)

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Phase II trial of ipilimumab in melanoma patients with preexisting humoural immune response to NY-ESO-1

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BACKGROUND: Immune checkpoint therapy has dramatically changed treatment options in patients with metastatic melanoma. However, a relevant part of patients still does not respond to treatment. Data regarding the prognostic or predictive significance of preexisting immune responses against tumour antigens are conflicting. Retrospective data suggested a higher clinical benefit of ipilimumab in melanoma patients with preexisting NY-ESO-1-specific immunity. PATIENTS AND METHODS: Twenty-five patients with previously untreated or treated metastatic melanoma and preexisting humoural immune response against NY-ESO-1 received ipilimumab at a dose of 10 mg/kg in week 1, 4, 7, 10 followed by 3-month maintenance treatment for a maximum of 48 weeks. Primary endpoint was the disease control rate (irCR, irPR or irSD) according to immune-related response criteria (irRC). Secondary endpoints included the disease control rate according to RECIST criteria, progression-free survival and overall survival (OS). Humoural and cellular immune responses against NY-ESO-1 were analysed from blood samples. RESULTS: Disease control rate according to irRC was 52%, irPR was observed in 36% of patients. Progression-free survival according to irRC was 7.8 months, according to RECIST criteria it was 2.9 months. Median OS was 22.7 months; the corresponding 1-year survival rate was 66.8%. Treatment-related grade 3 AEs occurred in 36% with no grade 4-5 AEs. No clear association was found between the presence of NY-ESO-1-specific cellular or humoural immune responses and clinical activity. CONCLUSION: Ipilimumab demonstrated clinically relevant activity within this biomarker-defined population. NY-ESO-1 positivity, as a surrogate for a preexisting immune response against tumour antigens, might help identifying patients with a superior outcome from immune checkpoint blockade. CLINICAL TRIAL INFORMATION: NCT01216696.

Author Info: (1) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. Electronic address: GeorgMartin.Haag@med.uni-heidelberg.de. (2) Department of Medical Oncology, National Center for

Author Info: (1) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. Electronic address: GeorgMartin.Haag@med.uni-heidelberg.de. (2) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (3) Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (4) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (5) Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (6) Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (7) Translational Immunology, National Center for Tumor Diseases, Heidelberg, Germany. (8) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (9) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (10) Translational Immunology, National Center for Tumor Diseases, Heidelberg, Germany. (11) Translational Immunology, National Center for Tumor Diseases, Heidelberg, Germany. (12) Translational Immunology, National Center for Tumor Diseases, Heidelberg, Germany. (13) Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany. (14) NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany. (15) NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany. (16) Translational Immunology, National Center for Tumor Diseases, Heidelberg, Germany; Regensburg Center for Interventional Immunology, University Hospital Regensburg, Germany. (17) Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Germany. (18) Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany; Clinical Cooperation Unit "Applied Tumor-Immunity", German Cancer Research Center (DKFZ), Heidelberg, Germany.

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Bispecific chimeric antigen receptors targeting the CD4 binding site and high-mannose Glycans of gp120 optimized for anti-human immunodeficiency virus potency and breadth with minimal immunogenicity

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BACKGROUND AIMS: Chimeric antigen receptors (CARs) offer great potential toward a functional cure of human immunodeficiency virus (HIV) infection. To achieve the necessary long-term virus suppression, we believe that CARs must be designed for optimal potency and anti-HIV specificity, and also for minimal probability of virus escape and CAR immunogenicity. CARs containing antibody-based motifs are problematic in the latter regard due to epitope mutation and anti-idiotypic immune responses against the variable regions. METHODS: We designed bispecific CARs, each containing a segment of human CD4 linked to the carbohydrate recognition domain of a human C-type lectin. These CARs target two independent regions on HIV-1 gp120 that presumably must be conserved on clinically significant virus variants (i.e., the primary receptor binding site and the dense oligomannose patch). Functionality and specificity of these bispecific CARs were analyzed in assays of CAR-T cell activation and spreading HIV-1 suppression. RESULTS: T cells expressing a CD4-dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DCSIGN) CAR displayed robust stimulation upon encounter with Env-expressing targets, but negligible activity against intercellular adhesion molecule (ICAM)-2 and ICAM-3, the natural dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin ligands. Moreover, the presence of the lectin moiety prevented the CD4 from acting as an entry receptor on CCR5-expressing cells, including CD8(+) T cells. However, in HIV suppression assays, the CD4-DCSIGN CAR and the related CD4-liver/lymph node-specific intercellular adhesion molecule-3-grabbing non-integrin CAR displayed only minimally increased potency compared with the CD4 CAR against some HIV-1 isolates and reduced potency against others. By contrast, the CD4-langerin and CD4-mannose binding lectin (MBL) CARs uniformly displayed enhanced potency compared with the CD4 CAR against all the genetically diverse HIV-1 isolates examined. Further experimental data, coupled with known biological features, suggest particular advantages of the CD4-MBL CAR. DISCUSSION: These studies highlight features of bispecific CD4-lectin CARs that achieve potency enhancement by targeting two distinct highly conserved Env determinants while lacking immunogenicity-prone antibody-based motifs.

Author Info: (1) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. (2) Laboratory of Viral Diseases, National

Author Info: (1) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. (2) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. (3) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. (4) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. (5) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. (6) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. (7) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. (8) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. (9) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: edward_berger@nih.gov.

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Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway

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PURPOSE: Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across pre-clinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven tumor immunity from hepatotoxicity. EXPERIMENTAL DESIGN: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without co-administration of checkpoint blockade, via 1) measurement of serum transaminase levels, 2) imaging of liver immune infiltrates, and 3) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines and chemokines. RESULTS: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27 that is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage, triggering transaminase elevation. FoxP3+ regulatory T cells limit liver damage, and their removal dramatically exacerbates 4-1BB agonist-induced hepatitis. Co-administration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma. CONCLUSIONS: 4-1BB agonist antibodies trigger hepatitis via activation and expansion of interleukin-27-producing liver Kupffer cells and monocytes. Co-administration of CTLA-4 and/or CCR2 blockade may minimize hepatitis, but yield equal or greater antitumor immunity.

Author Info: (1) Immunology, University of Texas MD Anderson Cancer Center. (2) Immunology, University of Texas MD Anderson Cancer Center. (3) Immunology Program, University of Texas Graduate

Author Info: (1) Immunology, University of Texas MD Anderson Cancer Center. (2) Immunology, University of Texas MD Anderson Cancer Center. (3) Immunology Program, University of Texas Graduate School of Biomedical Sciences at Houston. (4) Immunology, The University of Texas MD Anderson Cancer Center. (5) Immunology, The University of Texas MD Anderson Cancer Center. (6) Immunology, The University of Texas MD Anderson Cancer Center. (7) Immunology, The University of Texas MD Anderson Cancer Center. (8) Cancer Medicine, University of Texas MD Anderson Cancer Center. (9) Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center. (10) Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center. (11) Immunology Program, University of Texas Graduate School of Biomedical Sciences at Houston mcurran@mdanderson.org.

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p53-reactive T cells are associated with clinical benefit in patients with platinum-resistant epithelial ovarian cancer after treatment with a p53 vaccine and gemcitabine chemotherapy

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PURPOSE: To conduct a Phase I trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer. EXPERIMENTAL DESIGN: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses. RESULTS: 11 patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome and immunological response. TOXICITY: There were no DLTs but 3/11 patients came off study early due to gemcitabine-attributed adverse events (AEs). Minimal AEs were attributed to p53MVA vaccination. Immunological and Clinical Response: Enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T cell compartments in 5/11 and 6/11 patients respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity post therapy. Tumor shrinkage or disease stabilization occurred in 4 patients. CONCLUSIONS: p53MVA was well tolerated, but gemcitabine without steroid pre-treatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+T cell responses post therapy correlated with longer PFS. Therefore, if responses to p53MVA could be enhanced with alternative agents, superior clinical responses may be achievable.

Author Info: (1) Experimental Therapeutics, City of Hope. (2) Department of Information Sciences, City of Hope. (3) Information Sciences, City of Hope National Medical Center. (4) Department

Author Info: (1) Experimental Therapeutics, City of Hope. (2) Department of Information Sciences, City of Hope. (3) Information Sciences, City of Hope National Medical Center. (4) Department of Medical Oncology and Therapeutics Research, City Of Hope National Medical Center. (5) Hematology/Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center. (6) Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope. (7) Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope. (8) Ps Medical Oncology, City of Hope. (9) Department of Medical Oncology and Therapeutics Research, City Of Hope National Medical Center. (10) Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center. (11) Clinical Trials Office, City of Hope National Medical Center. (12) Clinical Trials Office, City Of Hope National Medical Center. (13) Antatomy Pathology, City of Hope National Medical Center. (14) General & Oncologic Surgery, City of Hope National Medical Center. (15) Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope ddiamond@coh.org. (16) Medical Oncology and Therapeutic Research, City of Hope.

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Exosomes associated with human ovarian tumors harbor a reversible checkpoint of T cell responses

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Nano-sized membrane-encapsulated extracellular vesicles isolated from the ascites fluids of ovarian cancer patients are identified as exosomes based on their biophysical and compositional characteristics. We report here that T cells pulsed with these tumor-associated exosomes during TCR-dependent activation inhibit various activation endpoints including translocation of NFkB and NFAT into the nucleus, upregulation of CD69 and CD107a, production of cytokines and cell proliferation. Additionally, the activation of virus-specific CD8+ T cells that are stimulated with the cognate viral peptides presented in the context of class I MHC is also suppressed by the exosomes. The inhibition occurs without loss of cell viability, and coincidentally with the binding and internalization of these exosomes. This exosome-mediated inhibition of T cells was transient and reversible: T cells exposed to exosomes can be reactivated once exosomes are removed. We conclude that tumor-associated exosomes are immunosuppressive, and represent a therapeutic target blockade of which would enhance the antitumor response of quiescent tumor-associated T cells and prevent the functional arrest of adoptively transferred tumor-specific T cells or chimeric antigen receptor (CAR) T cells.

Author Info: (1) Microbiology and Immunology, School of Medicine, University at Buffalo. (2) Microbiology and Immunology, School of Medicine, University at Buffalo. (3) Flow and Image Cytometry

Author Info: (1) Microbiology and Immunology, School of Medicine, University at Buffalo. (2) Microbiology and Immunology, School of Medicine, University at Buffalo. (3) Flow and Image Cytometry Shared Resource, Roswell Park Cancer Institute. (4) Pharmaceutical Sciences, University at Buffalo. (5) Microbiology and Immunology, School of Medicine, University at Buffalo. (6) Flow and Image Cytometry Shared Resource, Roswell Park Cancer Institute. (7) Flow Cytometry, Roswell Park Cancer Institute. (8) Gynecologic Oncology, Roswell Park Cancer Institute. (9) Pharmaceutical Sciences, University at Buffalo. (10) Microbiology and Immunology, School of Medicine, University at Buffalo rbankert@buffalo.edu.

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