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      Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition

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          Abstract

          Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1–mediated (PD-1–mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB–based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.

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          Author and article information

          Contributors
          Journal
          J Clin Invest
          J. Clin. Invest
          J Clin Invest
          The Journal of Clinical Investigation
          American Society for Clinical Investigation
          0021-9738
          1558-8238
          25 July 2016
          1 August 2016
          1 November 2016
          : 126
          : 8
          : 3130-3144
          Affiliations
          [1 ]Center for Cell Engineering and
          [2 ]Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
          [3 ]Protein Interactions Section, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland, USA.
          Author notes
          Address correspondence to: Prasad S. Adusumilli, Center for Cell Engineering, Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. Phone: 212.639.8093; E-mail: adusumip@ 123456mskcc.org .

          Authorship note: L. Cherkassky and A. Morello contributed equally to this work.

          Article
          PMC4966328 PMC4966328 4966328 83092
          10.1172/JCI83092
          4966328
          27454297
          4ac2884d-018c-4ba7-8473-0d70f8f491d7
          Copyright © 2016, American Society for Clinical Investigation
          History
          : 3 June 2015
          : 19 May 2016
          Categories
          Research Article

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