Portal de Periódicos da CAPES

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

2017; Elsevier BV; Volume: 130; Issue: 3 Linguagem: Inglês

10.1182/blood-2017-01-761320

1528-0020

Diogo Gomes‐Silva, Madhuwanti Srinivasan, Sandhya Sharma, Ciaran M. Lee, Dimitrios L. Wagner, Timothy Davis, Rayne H. Rouce, Gang Bao, Malcolm K. Brenner, Maksim Mamonkin,

Viral Infectious Diseases and Gene Expression in Insects

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.