TY - JOUR
T1 - Specific Targeting of Multiple Myeloma by Dual Split-signaling Chimeric Antigen Receptor T cells Directed against CD38 and CD138
AU - van der Schans, Jort J
AU - Wang, Ziyu
AU - van Arkel, Jennemiek
AU - van Schaik, Thijs
AU - Katsarou, Afroditi
AU - Ruiter, Ruud
AU - Baardemans, Thomas
AU - Yuan, Huipin
AU - de Bruijn, Joost
AU - Zweegman, Sonja
AU - van de Donk, Niels W C J
AU - Groen, Richard W J
AU - Themeli, Maria
AU - Mutis, Tuna
N1 - Funding Information: J.J. van der Schans, J. van Arkel, and Z. Wang were financially supported by “Stichting Kompass” and KWF, grant number 12967. Publisher Copyright: ©2023 American Association for Cancer Research.
PY - 2023/10/15
Y1 - 2023/10/15
N2 - Purpose: The success of B-cell maturation antigen (BCMA)specific chimeric antigen receptor (CAR) T cells illustrates the potential of this novel therapy for multiple myeloma. Nonetheless, broadening CAR T-cell therapy beyond BCMA requires inventive strategies as there are only a few multiple myeloma– or plasma cell–specific target antigens. We investigated the feasibility of achieving multiple myeloma specificity by dual-split CD38/CD138 CAR targeting, whereby the stimulatory and costimulatory signals for T-cell activation are split into two separate stimulatory (sCAR) and costimulatory CARs (cCAR). Experimental Design: Using various combinations of CD38 and CD138 sCARs and cCARs with different affinities, we generated several dual-split CAR T cells and analyzed them for multiple myeloma–specific effector functions in vitro. The best-functioning CAR T cells were tested in vivo in a murine xenograft model. Results: We found optimal designs of both CD38sCAR/ CD138cCAR and CD138sCAR/CD38cCAR combinations, that effectively lysed multiple myeloma cells but spared single CD38- or CD138-positive healthy hematopoietic cells. While the CD38sCAR/ CD138cCAR T cells achieved multiple myeloma–specific activity solely due to the low affinity of the CD38sCARs, the multiple myeloma–specific cytotoxicity, cytokine release, and proliferation of CD138sCAR/CD38cCAR T cells were established through a true combinatorial stimulatory and costimulatory effect. The most optimal combination comprised a low-affinity CD138sCAR combined with a high-affinity CD38cCAR. These CD138sCAR/CD38cCAR T cells also showed dual-antigen specific anti–multiple myeloma effects in vivo. Importantly, they were also effective against multiple myeloma cells from daratumumab pretreated patients with decreased CD38 expression levels. Conclusions: We demonstrate the possibility to specifically target multiple myeloma cells, even after CD38 targeted therapy, with carefully-designed dual-split CARs directed against CD38 and CD138.
AB - Purpose: The success of B-cell maturation antigen (BCMA)specific chimeric antigen receptor (CAR) T cells illustrates the potential of this novel therapy for multiple myeloma. Nonetheless, broadening CAR T-cell therapy beyond BCMA requires inventive strategies as there are only a few multiple myeloma– or plasma cell–specific target antigens. We investigated the feasibility of achieving multiple myeloma specificity by dual-split CD38/CD138 CAR targeting, whereby the stimulatory and costimulatory signals for T-cell activation are split into two separate stimulatory (sCAR) and costimulatory CARs (cCAR). Experimental Design: Using various combinations of CD38 and CD138 sCARs and cCARs with different affinities, we generated several dual-split CAR T cells and analyzed them for multiple myeloma–specific effector functions in vitro. The best-functioning CAR T cells were tested in vivo in a murine xenograft model. Results: We found optimal designs of both CD38sCAR/ CD138cCAR and CD138sCAR/CD38cCAR combinations, that effectively lysed multiple myeloma cells but spared single CD38- or CD138-positive healthy hematopoietic cells. While the CD38sCAR/ CD138cCAR T cells achieved multiple myeloma–specific activity solely due to the low affinity of the CD38sCARs, the multiple myeloma–specific cytotoxicity, cytokine release, and proliferation of CD138sCAR/CD38cCAR T cells were established through a true combinatorial stimulatory and costimulatory effect. The most optimal combination comprised a low-affinity CD138sCAR combined with a high-affinity CD38cCAR. These CD138sCAR/CD38cCAR T cells also showed dual-antigen specific anti–multiple myeloma effects in vivo. Importantly, they were also effective against multiple myeloma cells from daratumumab pretreated patients with decreased CD38 expression levels. Conclusions: We demonstrate the possibility to specifically target multiple myeloma cells, even after CD38 targeted therapy, with carefully-designed dual-split CARs directed against CD38 and CD138.
UR - http://www.scopus.com/inward/record.url?scp=85175352106&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/1078-0432.CCR-23-0132
DO - https://doi.org/10.1158/1078-0432.CCR-23-0132
M3 - Article
C2 - 37527004
SN - 1078-0432
VL - 29
SP - 4219
EP - 4229
JO - Clinical cancer research : an official journal of the American Association for Cancer Research
JF - Clinical cancer research : an official journal of the American Association for Cancer Research
IS - 20
ER -