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

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          Abstract

          Extending the success of CAR T cells to T-cell malignancies is problematic since 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- and 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 due to 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 CAR 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
          American Society of Hematology
          1528-0020
          0006-4971
          May 24 2017
          Affiliations
          [1 ] Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, United States.
          [2 ] Department of Bioengineering, Rice University, Houston, TX, United States.
          [3 ] Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, United States; mamonkin@bcm.edu.
          Article
          blood-2017-01-761320
          10.1182/blood-2017-01-761320
          28539325

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