Dual chimeric antigen receptor T cells targeting CD38 and SLAMF7 with independent signalling demonstrate efficacy and safety in preclinical models of Multiple Myeloma

Abstract Chimeric antigen receptor T-cell (CAR-T) therapy for multiple myeloma (MM) targeting B-cell maturation antigen (BCMA) induces high overall response rates. However, relapse still occurs and novel strategies for targeting MM cells by CAR-T are needed. SLAMF7 (CS1) and CD38 on tumour plasma cells represent potential alternative targets for CAR-T in MM, but their expression on activated T cells and other hematopoietic cells raises concerns about the efficacy and safety of such treatments. Here, we used CRISPR/Cas9 deletion of the CD38 gene in T cells and developed DCAR, a double CAR system targeting CD38 and CS1 through activation and co-stimulation receptors, respectively. We show that inactivation of CD38enhances the anti-MM activity of DCAR-T in vitro. Edited DCAR-T showed strong in vitro and in vivo responses specifically against target cells expressing both the CD38 and the CS1 antigens. Importantly, we provide evidence that, unlike anti-CD38 CAR-T, which elicited a rapid immune reaction against hematopoietic cells in a humanized mouse model, DCAR-T showed no signs of toxicity. Thus, DCAR-T could provide a safe and efficient alternative to treat MM patients.