Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma

Eugenia Zah, Eunwoo Nam, Vinya Bhuvan, Uyen Tran, Brenda Y. Ji, Stanley B. Gosliner, Xiuli Wang, Christine E. Brown and Yvonne Y. Chen ()
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Eugenia Zah: University of California–Los Angeles
Eunwoo Nam: University of California–Los Angeles
Vinya Bhuvan: University of California–Los Angeles
Uyen Tran: University of California–Los Angeles
Brenda Y. Ji: University of California–Los Angeles
Stanley B. Gosliner: University of California–Los Angeles
Xiuli Wang: City of Hope Beckman Research Institute and Medical Center
Christine E. Brown: City of Hope Beckman Research Institute and Medical Center
Yvonne Y. Chen: University of California–Los Angeles

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies, yet marked vulnerability to antigen escape and tumor relapse exists. Here we report the rational design and optimization of bispecific CAR-T cells with robust activity against heterogeneous multiple myeloma (MM) that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit superior CAR expression and function compared to T cells that co-express individual BCMA and CS1 CARs. Combination therapy with anti–PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, while CAR-T cell treatment alone achieves durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets.

Date: 2020
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DOI: 10.1038/s41467-020-16160-5

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