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Published on: November 12, 2019
A compound chimeric antigen receptor strategy for targeting multiple myeloma
1iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY, USA.
Abstract:
Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.
Insights
Chimeric antigen receptor (CAR) T-cells targeting BCMA and CS1 show potent anti-myeloma activity. This dual-targeting CAR therapy may overcome antigen loss relapse and improve patient survival in multiple myeloma.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Current chimeric antigen receptor (CAR) T-cell therapies for multiple myeloma targeting BCMA (CD269) show initial efficacy but are limited by antigen loss and relapse.
- Relapse in multiple myeloma is often due to the emergence of BCMA-negative or -low expressing cells.
- Improved CAR T-cell designs are needed to address antigen escape and enhance long-term persistence.
Purpose of the Study:
- To develop and evaluate a novel compound CAR (cCAR) T-cell therapy targeting two distinct multiple myeloma antigens, BCMA and CS1.
- To assess the in vitro and in vivo anti-tumor activity of the dual-targeting cCAR T-cells against multiple myeloma.
- To determine if targeting both BCMA and CS1 can overcome antigen loss and improve therapeutic outcomes compared to single-target CARs.
Main Methods:
- Development of a compound CAR (cCAR) T-cell construct with two independent receptors targeting BCMA and CS1.
- In vitro assessment of cCAR T-cell cytotoxicity against multiple myeloma cell lines expressing BCMA and/or CS1.
- In vivo evaluation of cCAR T-cell efficacy and survival in multiple mouse models of multiple myeloma, including mixed antigen-expressing populations.
Main Results:
- The developed cCAR T-cells demonstrated potent and directed cytotoxicity against both BCMA-positive and CS1-positive multiple myeloma cells in vitro.
- In vivo studies using mouse models showed superior anti-tumor activity and improved survival with cCAR T-cells compared to single-target CAR T-cells.
- The cCAR T-cells effectively targeted mixed cell populations, indicating efficacy against both antigen-positive and potentially antigen-loss variants.
Conclusions:
- Compound targeting of BCMA and CS1 using cCAR T-cells is a promising strategy to enhance therapeutic responses in multiple myeloma.
- This dual-targeting approach may overcome antigen loss, a common mechanism of relapse, and broaden CAR therapy coverage.
- Further development of this cCAR T-cell therapy could lead to more durable remissions and improved outcomes for multiple myeloma patients.
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