Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma
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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.
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CAR-T cells targeting GPRC5D, CD19, CD38, CD138, CS1, and NKG2D are under exploration for MM treatment.
“Several CAR-T cells targeting antigens, such an GPRC5D [229–231], CD19 [232, 233], CD38 [234–236], CD138 [237], CS1 [238–240] and NKG2D [241, 242] are also under exploration for their efficacy in MM treatment.”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [238]
α-PD-1/PD-L1 enhanced CAR-T cell therapy by rescuing CAR-T cell exhaustion.
“α-PD-1/PD-L1 enhanced CAR-T cell therapy by rescuing CAR-T cell exhaustion [341–343].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [343]
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- Authors
- Zah, E., Nam, E., Bhuvan, V., Tran, U., Ji, B. Y., Gosliner, S. B., Wang, X., Brown, C. E., & Chen, Y. Y.
- Affiliations
- Amgen (United States) (US)
- University of California, Los Angeles (US)
- City Of Hope National Medical Center (US)
- Corresponding author
- Chen, Yvonne Y.
- Venue
- Nature Communications
- Published
- 2020-05-08
- Volume
- 11
- Issue
- 1
- Pages
- 2283-2283
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7210316
- OpenAlex
- W3022509419
- Cited by
- 222
- References
- 51
- Citations by year
- 2026: 20 · 2025: 25 · 2024: 52 · 2023: 25 · 2022: 47 · 2021: 37 · 2020: 14
- FWCI
- 11.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- UC | University of California, Los Angeles
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Keywords
- bispecific CAR T cells, BCMA, CS1, multiple myeloma, chimeric antigen receptor, antigen escape, tumor recurrence, anti-PD-1 combination therapy, tumor rechallenge
- MeSH terms
- Gene Editing, Receptors, Chimeric Antigen, Antigens, Neoplasm, Cytotoxicity, Immunologic, Humans, Immunologic Memory, Multiple Myeloma, T-Lymphocytes, Immunotherapy, Adoptive, K562 Cells, B-Cell Maturation Antigen, Programmed Cell Death 1 Receptor
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