Abstract There have been significant advances in therapy for multiple myeloma (MM). The development of chimeric antigen receptor (CAR) engineered T cells have shown incredible responses by harnessing anti-tumor activity of T cells. However, most CAR-T therapies targeting BCMA involve long manufacturing and expansion times impacting its utility as well as outcome. In a phase 1 clinical trial (NCT04318327) of dose escalation study, we treated 55 RRMM patients, using the next-generation T-charge platform to generate anti-BCMA CAR-T cells in less than 2 days by reducing ex-vivo processing and enhancing in-vivo expansion and preserving T-cell stemness. As we reported earlier, the overall response rate was 98%, and the complete response rate was 55% (Sperling et al ASCO, 2023). Our earlier reports also showed that T-cell stemness is preserved, with CAR T cells expanding robustly in peripheral blood of patients with high clone diversity (Shuntaro et al ASH, 2024). To identify CAR related features that can predict for longer-term response, we performed the immune-monitoring study, evaluating the CAR-T cell-activation and functional activity in bone marrow (BM) microenvironment at 3 months following infusion of PHE885 using CyTOF analysis for 74 markers from 32 patients. We specifically evaluated the association of functional fitness of CAR-T cells in patients with sCR 2 years (N=8, 27%) compared to patients who progressed (PD, N=24) within 2 years. We observed significant reduction in percentages of regulatory T cell population in CAR+ T cells in BM of sCR patients compared with PD patients (8% vs 18% respectively; p0.05). We also observed significantly higher expressions of activation markers CD38 (69% vs 31%), CD28 (58% vs 32%) and CD27 (68% vs 48%) on CAR+ T cells in sCR patients compared to PD patients (p0.05). Interestingly, we observed significantly higher expression of TIM-4 in CAR+ T cells in sCR patients (38% vs 8%; p0.05), indicating that CAR-T cells in sCR patients have reduced apoptosis. Furthermore, sCR patients have significantly higher population of CAR+ T cells producing IL-2 (46% vs 16%) and granzyme-B (59% vs 28%) and higher frequency of IL-10-producing cells (43% vs 10%) compared with PD patients (p0.05), suggesting higher proliferative and killing capacity as well as enhanced mitochondrial fitness. In summary, our results suggest that higher expression of activation markers and cytotoxic/proliferating cytokines in CAR-T cells is associated with sustained sCR of 2 years. Interestingly, these CAR-T cells show less susceptibility to apoptosis and exhibit better mitochondrial fitness. Taken together, we conclude that these functional phenotypes of CAR-T cells in bone marrow might potentially be contributing to sustained outcomes following therapy.
Potluri et al. (Mon,) studied this question.