Data from Specific targeting of Multiple Myeloma by Dual Split-signaling Chimeric Antigen Receptors T-cells directed against CD38 and CD138

• DOI: 10.1158/1078-0432.c.6879405
• Publication Date: 2023-10-13T07:41:29Z
• Authors: Jort J. van der S...; Ziyu Wang; Jennemiek van Arkel; Thijs van Schaik; Afroditi Katsarou; Ruud Ruiter; Thomas Baardemans; Huipin Yuan; Joost de Bruijn; Sonja Zweegman; Niels W.C.J. van ...; Richard W.J. Groen; Maria Themeli; Tuna Mutis

<div>Abstract<p>Purpose: The success of BCMA-specific chimeric antigen receptor (CAR) T-cells illustrates the potential this novel therapy for multiple myeloma (MM). Nonetheless, broadening CAR T-cell beyond BCMA requires inventive strategies as there are only a few MM- or plasma cell-specific target antigens. We investigated feasibility achieving MM specificity by dual-split CD38/CD138 targeting, whereby stimulatory and costimulatory signals activation split into two separate (sCAR) CARs (cCAR). Experimental Design: Using various combinations CD38 CD138 sCARs cCARs with different affinities, we generated several analyzed them MM-specific effector functions <i>in vitro</i>. best-functioning were tested vivo</i> in murine xenograft model. Results: found optimal designs both CD38sCAR/CD138cCAR CD138sCAR/CD38cCAR combinations, that effectively lysed cells, but spared single positive healthy hematopoietic cells. While achieved activity solely due to low affinity CD38sCARs, cytotoxicity, cytokine release, proliferation T‑cells established through true combinatorial effect. most combination comprised CD138sCAR combined high CD38cCAR. These also showed dual-antigen specific anti-MM effects vivo. </i>Importantly, they effective against cells from daratumumab pre-treated patients decreased expression levels. Conclusions: demonstrate possibility specifically even after targeted therapy, carefully-designed directed CD138.</p></div>