TY - JOUR
T1 - CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies
AU - Gomes-Silva, Diogo
AU - Srinivasan, Madhuwanti
AU - Sharma, Sandhya
AU - Lee, Ciaran M.
AU - Wagner, Dimitrios L.
AU - Davis, Timothy H.
AU - Rouce, Rayne H.
AU - Bao, Gang
AU - Brenner, Malcolm
AU - Mamonkin, Maksim
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/7/20
Y1 - 2017/7/20
N2 - 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 (CD71) 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.
AB - 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 (CD71) 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.
UR - http://www.scopus.com/inward/record.url?scp=85025463342&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85025463342&partnerID=8YFLogxK
U2 - 10.1182/blood-2017-01-761320
DO - 10.1182/blood-2017-01-761320
M3 - Article
C2 - 28539325
AN - SCOPUS:85025463342
SN - 0006-4971
VL - 130
SP - 285
EP - 296
JO - Blood
JF - Blood
IS - 3
ER -