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      Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition

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          Abstract

          Purpose

          Using gene-disrupted allogeneic T cells as universal effector cells provides an alternative to and potentially improves current chimeric antigen receptor (CAR) T cell therapy against cancers and infectious diseases.

          Experimental Design

          The CRISPR/Cas9 system has recently emerged as a simple and efficient way for multiplex genome engineering. By combining the lentiviral delivery of CAR and CRISPR RNA electroporation to co-introduce RNA encoding the Cas9 and gRNAs targeting endogenous TCR, beta-2 microglobulin (B2M) and PD1 simultaneously, to generate gene-disrupted allogeneic CAR T cells deficient of TCR, HLA class I molecule and PD1.

          Results

          The CRISPR gene-edited CAR T cells showed potent anti-tumor activities, both in vitro and in animal models and were as potent as non-gene edited CAR T cells. In addition the TCR and HLA class I double deficient T cells had reduced alloreactivity and did not cause graft-versus-host disease. Finally, simultaneous triple genome editing by adding the disruption of PD1 led to enhanced in vivo anti-tumor activity of the gene-disrupted CART cells.

          Conclusions

          Gene-disrupted allogeneic CAR and TCR T cells could provide an alternative as a universal donor to autologous T cells, which carry difficulties and high production costs. Gene-disrupted CAR and TCR T cells with disabled checkpoint molecules may be potent effector cells against cancers and infectious diseases.

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          Author and article information

          Journal
          9502500
          8794
          Clin Cancer Res
          Clin. Cancer Res.
          Clinical cancer research : an official journal of the American Association for Cancer Research
          1078-0432
          16 November 2016
          04 November 2016
          01 May 2017
          01 May 2018
          : 23
          : 9
          : 2255-2266
          Affiliations
          [1 ]Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
          [2 ]Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
          [3 ]Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
          Author notes
          [* ]To whom correspondence should be addressed: Yangbing Zhao, M.D., Ph.D., University of Pennsylvania School of Medicine, Center for Cellular Immunotherapies, 3400 Civic Center Blvd, TRC 421, RM08-122, Philadelphia, PA 19104-5156, Yangbing@ 123456exchange.upenn.edu Or Carl H. June, M.D., University of Pennsylvania School of Medicine, Center for Cellular Immunotherapies, 3400 Civic Center Blvd, TRC 421, RM08-121, Philadelphia, PA 19104-5156, cjune@ 123456exchange.upenn.edu
          Article
          PMC5413401 PMC5413401 5413401 nihpa828188
          10.1158/1078-0432.CCR-16-1300
          5413401
          27815355
          ee6af8b9-59ff-4238-9113-b28110cfc367
          History
          Categories
          Article

          CRISPR/Cas9,T lymphocytes,PD1,Chimeric antigen receptors,Universal T cells

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