Journal Articles

Experimental Immunotherapy

Preclinical and clinical cancer immunotherapy approaches

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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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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T cell responses in the microenvironment of primary renal cell carcinoma - Implications for adoptive cell therapy

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In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC) are infiltrated with tumor-reactive T cells that could be efficiently employed for adoptive transfer immunotherapy. TILs and autologous tumor cell lines (TCLs) were successfully generated from 22 (92%) and 17 (77%) of 24 consecutive primary RCC specimens and compared to those generated from MM. Immune recognition of autologous TCLs or fresh tumor digests (FTD) was observed in CD8+ TILs from 82% of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, poly-functionality, and ability to expand in classical expansion protocols of CD8+ T-cell responses was lower compared to MM-TILs. The RCC-TILs that did react to the tumor were functional and antigen presentation and processing on RCC-tumors was similar to MM-TILs. Direct recognition of tumors with cytokine-induced overexpression of human leukocyte antigen (HLA) class II was observed from CD4+ T cells (6/12; 50%). Thus, TILs from primary RCC specimens could be isolated, expanded, and could recognize tumors. However, immune responses of expanded CD8+ RCC-TILs were typically weaker than MM-TILs and displayed a mono-/oligo- functional pattern. The ability to select, enrich, and expand tumor-reactive poly-functional T cells may be critical in developing effective ACT with TILs for RCC.

Author Info: (1) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen. (2) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital

Author Info: (1) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen. (2) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen. (3) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen. (4) Institute of Medical Immunology, Martin Luther University Halle-Wittenberg. (5) Division for Immunology and Vaccinology, Technical University of Denmark. (6) Division for Immunology and Vaccinology, Technical University of Denmark. (7) Department of Oncology, Herlev Hospital, University of Copenhagen. (8) Institute of Medical Immunology, Martin Luther University Halle-Wittenberg. (9) Department of Urology, Herlev Hospital, University of Copenhagen. (10) Department of Pathology, Herlev Hospital, University of Copenhagen. (11) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen. (12) Department of Hematology, Center for Cancer Immune Therapy, Herlev Hospital, University of Copenhagen inge.marie.svane@regionh.dk.

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Transcriptional retargeting of herpes simplex virus for cell-specific replication to control cancer

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INTRODUCTION: Oncolytic virotherapy has emerged as a novel frontier in the treatment of cancer. Among the viruses that entered clinical trials are the oncolytic herpes simplex virus-1 (HSV-1). Current oncolytic HSV-1 approved for clinical practice, and those in clinical trials are attenuated viruses, often deleted in the neurovirulence gene gamma134.5, and in additional genes, which may result in a much more attenuated virus with reduced replication efficiency. Therefore, the transcriptional retargeting strategy by modifying the regulator elements flanking essential viral genes to achieve tumor-specific replication while maintaining as much of the viral genome has been representing alternative promising oncolytic virotherapy modality. MATERIALS AND METHODS: In this communication, we aimed to review extensive studies on transcriptional retargeting strategy with HSV-1 genome engineered on immediate-early ICP4 gene, late gamma134.5 gene or early ICP6 gene as well as multiple-regulated oncolytic HSV1 through combining transcriptional retargeting and translational control. Design modality based on differential cellular background, advantage, and potential clinic limitation of the innovative oncolytic HSV-1 was described, and prospective and challenge of transcriptional retargeting strategy were collectively summarized. CONCLUSION: Transcriptional retargeting strategy holds great promise in retaining tumor specificity as well as full replication capacity of oncolytic virus in the target cell as urgently required by clinical trials. Future efforts should be aimed toward the development of multiple-component targeted oncolytic virus such as combing the transcriptional retargeting strategy and genetically attenuated modulation or post-transcriptional control that will be the most effective at generating truly tumor selective vectors.

Author Info: (1) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. Shanghai Key Laboratory of Gynecologic Oncology

Author Info: (1) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. (2) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. (3) Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA. (4) Viri Biotechnology Company Limited, No. 8 Guohuai Street, Zhengzhou, Henan, 450052, China. (5) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. diwen163@163.com. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. diwen163@163.com. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA. diwen163@163.com. Viri Biotechnology Company Limited, No. 8 Guohuai Street, Zhengzhou, Henan, 450052, China. diwen163@163.com. (6) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. ningning1723@126.com. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. ningning1723@126.com.

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Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma

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Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (p=0.012), which encodes a subunit of a SWI/SNF chromatin remodeling complex (the PBAF subtype). We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-(L)1 blockade therapy alone or in combination with anti-CTLA-4 therapies (p=0.0071). Gene expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK/STAT, hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor cell expression profiles to influence responsiveness to immune checkpoint therapy.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (4) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (5) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (10) Bristol-Myers Squibb, New York, NY 10154, USA. (11) Bristol-Myers Squibb, New York, NY 10154, USA. (12) Bristol-Myers Squibb, New York, NY 10154, USA. (13) Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Columbia University Medical Center, New York, NY 10032, USA. (17) James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (18) James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (19) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (20) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (21) Mayo Clinic, Scottsdale, AZ 85259, USA. (22) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (25) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. eliezerm_vanallen@dfci.harvard.edu toni_choueiri@dfci.harvard.edu. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. eliezerm_vanallen@dfci.harvard.edu toni_choueiri@dfci.harvard.edu. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.

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A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing

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Many human cancers are resistant to immunotherapy for reasons that are poorly understood. We used a genome-scale CRISPR/Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. Inactivation of >100 genes sensitized mouse B16F10 melanoma cells to killing by T cells, including Pbrm1, Arid2 and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex. Loss of PBAF function increased tumor cell sensitivity to interferon-gamma, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (3) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (4) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (7) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (12) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (13) Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. kai_wucherpfennig@dfci.harvard.edu xsliu@jimmy.harvard.edu. (16) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. kai_wucherpfennig@dfci.harvard.edu xsliu@jimmy.harvard.edu. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.

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Tumour endothelial marker 1/endosialin-mediated targeting of human sarcoma

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BACKGROUND: Tumour endothelial marker 1 (TEM1/endosialin/CD248) is a tumour-restricted cell-surface protein expressed by human sarcomas. We previously developed a high-affinity human single-chain variable fragment (scFv)-Fc fusion protein (78Fc) against TEM1 and demonstrated its specific binding to human and mouse TEM1. PATIENT AND METHODS: Clinical sarcoma specimens were collected between 2000 and 2015 at the Hospital of the University of Pennsylvania, as approved by the institutional review board and processed by standard formalin-fixed paraffin embedded techniques. We analysed TEM1 expression in 19 human sarcoma subtypes (n = 203 specimens) and eight human sarcoma-cell lines. Near-infrared (NIR) imaging of tumour-bearing mice was used to validate 78Fc binding to TEM1(+) sarcoma in vivo. Finally, we tested an immunotoxin conjugate of anti-TEM1 78Fc with saporin (78Fc-Sap) for its therapeutic efficacy against human sarcoma in vitro and in vivo. RESULTS: TEM1 expression was identified by immunohistochemistry in 96% of human sarcomas, of which 81% expressed TEM1 both on tumour cells and the tumour vasculature. NIR imaging revealed specific in vivo targeting of labelled 78Fc to TEM1(+) sarcoma xenografts. Importantly, 78Fc-Sap was effective in killing in vitro TEM1(+) sarcoma cells and eliminated human sarcoma xenografts without apparent toxicity in vivo. CONCLUSION: TEM1 is an important therapeutic target for human sarcoma, and the high-affinity TEM1-specific scFv fusion protein 78Fc is suitable for further clinical development for therapeutic applications in sarcoma.

Author Info: (1) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (2) Ovarian Cancer Research Center

Author Info: (1) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (2) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (3) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (4) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (5) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (6) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (7) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (8) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (9) Department of Pathology, People's Hospital, Peking University, PR China; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (10) Department of Obstetrics and Gynecology, Tongji Hospital, Tongji University, PR China. (11) Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (12) Department of Pathology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. (13) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University of Lausanne, 1007-CH, Switzerland. (14) Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University of Lausanne, 1007-CH, Switzerland. (15) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Ludwig Institute for Cancer Research, University of Lausanne and Department of Oncology, University of Lausanne, 1007-CH, Switzerland. Electronic address: george.coukos@chuv.ch. (16) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA. Electronic address: lich@mail.med.upenn.edu.

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