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 - Funding Information:
The authors thank Michael Gundry and Lorenzo Brunetti for technical assistance with genome editing, Stephen Gottschalk for providing NALM6 cells, Haruko Tashiro for technical assistance with ELISPOT assays, Harshavardhan Deshmukh for assistance with cell culture work, Carlos Ramos and Joaquim Cabral for support, and Catherine Gillespie for editing the manuscript. This work was supported by an American Society of Hematology Scholar Award (M.M.) and by the National Institutes of Health, National Cancer Institute (P50 CA126752), as well as by the Cancer Prevention and Research Institute of Texas (RR140081) (G.B.). D.G.-S. acknowledges Fundação para a Ciência e Tecnologia (Portugal) for financial support (SFRH/BD/52479/2014). The authors also appreciate the support of shared resources from the Cancer Center (support grant P30CA125123).
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.
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U2 - 10.1182/blood-2017-01-761320
DO - 10.1182/blood-2017-01-761320
M3 - Article
C2 - 28539325
AN - SCOPUS:85025463342
VL - 130
SP - 285
EP - 296
JO - Blood
JF - Blood
SN - 0006-4971
IS - 3
ER -