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

Author

Listed:
  • Eugenia Zah

    (University of California–Los Angeles
    Amgen)

  • 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
    University of California–Los Angeles
    Parker Institute for Cancer Immunotherapy Center at UCLA)

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.

Suggested Citation

  • Eugenia Zah & Eunwoo Nam & Vinya Bhuvan & Uyen Tran & Brenda Y. Ji & Stanley B. Gosliner & Xiuli Wang & Christine E. Brown & Yvonne Y. Chen, 2020. "Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16160-5
    DOI: 10.1038/s41467-020-16160-5
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