No abstract

Chimeric antigen receptor T cells (CAR-T) have provided promising results in multiple myeloma (MM). However, many patients still relapse, pointing toward the need of improving this therapy. Here, we analyzed peripheral blood T cells from MM patients at different stages of the disease and investigated their phenotype and capacity to generate functional CAR-T directed against CS1 or B Cell Maturation antigen. We found a decrease in naive T cells and elevated frequencies of exhaustion markers in T cells from treated MM patients. Interestingly, individuals treated with daratumumab display elevated ratios of central memory T cells. CAR-T derived from patients at relapse show reduced in vitro expansion and cytotoxic capacities in response to MM cells compared to those produced at diagnosis. Of note, CAR-T from daratumumab treated patients display intermediate defects. Reduced anti-myeloma activity of CAR T cells from treated patients was also observed in a mouse model. Our findings suggest that T cell defects in MM patients, specifically during relapse, have a major impact on their capacity to generate efficient therapeutic CAR-T. Selecting naive or central memory T cell subsets to generate therapeutic T cells could improve the CAR-T therapy for MM.

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.