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      CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies

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          Key Points

          • Genomic disruption of CD7 prior to CAR transduction allows generation of CD7 CAR T cells without extensive self-antigen-driven fratricide.

          • CD7 CAR T cells have robust activity against T-cell malignancies in vitro and in vivo.

          Abstract

          Extending the success of chimeric antigen receptor (CAR) T cells to T-cell malignancies is problematic because most target antigens are shared between normal and malignant cells, leading to CAR T-cell fratricide. CD7 is a transmembrane protein highly expressed in acute T-cell leukemia (T-ALL) and in a subset of peripheral T-cell lymphomas. Normal expression of CD7 is largely confined to T cells and natural killer (NK) cells, reducing the risk of off-target-organ toxicity. Here, we show that the expression of a CD7-specific CAR impaired expansion of transduced T cells because of residual CD7 expression and the ensuing fratricide. We demonstrate that targeted genomic disruption of the CD7 gene prevented this fratricide and enabled expansion of CD7 CAR T cells without compromising their cytotoxic function. CD7 CAR T cells produced robust cytotoxicity against malignant T-cell lines and primary tumors and were protective in a mouse xenograft model of T-ALL. Although CD7 CAR T cells were also toxic against unedited (CD7 +) T and NK lymphocytes, we show that the CD7-edited T cells themselves can respond to viral peptides and therefore could be protective against pathogens. Hence, genomic disruption of a target antigen overcomes fratricide of CAR T cells and establishes the feasibility of using CD7 CAR T cells for the targeted therapy of T-cell malignancies.

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          Author and article information

          Journal
          Blood
          Blood
          bloodjournal
          blood
          Blood
          Blood
          American Society of Hematology (Washington, DC )
          0006-4971
          1528-0020
          20 July 2017
          24 May 2017
          20 July 2018
          : 130
          : 3
          : 285-296
          Affiliations
          [1 ]Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX;
          [2 ]Texas Children's Hospital, Houston, TX;
          [3 ]Houston Methodist Hospital, Houston, TX;
          [4 ]Department of Bioengineering and Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal;
          [5 ]Department of Bioengineering, Rice University, Houston, TX; and
          [6 ]Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX
          Author information
          http://orcid.org/0000-0002-9615-3735
          http://orcid.org/0000-0001-7178-8163
          Article
          PMC5520470 PMC5520470 5520470 2017/761320
          10.1182/blood-2017-01-761320
          5520470
          28539325
          85ba0f00-b4a3-486b-974e-f02a5b4c2eba
          © 2017 by The American Society of Hematology
          History
          : 09 January 2017
          : 21 May 2017
          Page count
          Pages: 12
          Funding
          Funded by: National Institutes of Health;
          Categories
          12
          Immunobiology
          Custom metadata
          free

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