Professor Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, United States
Introduction: Bispecific CAR-T cell therapy has been proposed to mitigate some limitations of single-targeted CAR-T cells. CS1 plays a vital role in myeloma pathogenesisand is also highly expressed on tumor cells in almost all patients (pts) with multiple myeloma (MM). Therefore, we aim to augment BCMA targeting with CS1. Here we report the outcomes of 16 pts with refractory or relapsed (RR) MM in our phase I clinical trial (NCT04662099).
Methods: CS1-BCMA bispecific CAR contains a murine anti-CS1 scFv (clone 7A8D5) and a murine anti-BCMA scFv (clone 4C8) in tandem, and a 4-1BB costimulatory domain. The enrolled pts must have received at least 2 prior lines of therapy, and previous BCMA- or CS1-targeted immunotherapies were allowed. Pts were subjected to lymphodepleting regimens with cyclophosphamide and fludarabine daily prior to the CAR-T infusion. Planned dose levels were 0.75x106, 1.5x106, and 3.0x106 CAR+T cells/kg, and repeated infusions were allowed. Primary objectives were incidence of AE, CRS and ICANS. Secondary objectives were ORR, OS, DOR, and PFS. Other objectives included in vivo kinetics of CAR-T cells, changes of soluble BCMA, immune assessment before and after infusion.
Results: 16 patients received the infusion of CS1-BCMA CAR-T cells and were included in the final analysis. Nine pts (56%) carried cytogenetic abnormalities, and 3 pts had EMD alone without detectable MM cells in BM. BCMA and CS1 were highly expressed on MM cells in BM by flow cytometry (mean BCMA+76.7% and CS1+ 96.5%) and EMD by trichromatic immunofluorescence. Nine pts (56%) were refractory, and 7 pts (44%) were relapsed and refractory. The median prior lines of treatment were 5.4 (range 2-10). All pts (100%) were exposed to bortezomib, 6 (38%) to ixazomib and 1 (6%) to cafilzomib. 13 pts (81%) received lenalidomide, 6 (38%) received thalidomide and 5 (31%) received pomadomide. 7 pts (44%) received autologous transplantation, 6 (38%) were exposed to daratumumab, 2 (13%) received selinexor and 2 (13%) had previous BCMA-targeted CAR-T cell therapy. Six pts (38%) experienced CRS. Grade 3 CRS occurred once and lasted for 5 days. ICANS was not observed. The ORR was 81% (13/16) for all patients, including 6 stringent complete, 3 very good partial, and 4 partial responses. The ORR was 100% (13/13) for patients with MM cells in BM. Pt 16 had received prior anti-BCMA CAR-T treatment and achieved PR after CS1-BCMA CAR-T infusion. Soluble BCMA decreased remarkably in peripheral blood (PB) and BM after infusion. The median OS, PFS and DOR weren’t reached, and OS, PFS and DOR at 12-month were 83.9%, 55.2% and 68.8%, respectively. On day 14 after infusion, CAR-T cells peaked at 138245 copies/ug DNA in PB (n=16) and 86654 copies/ug DNA in BM (n=13) by droplet digital PCR.CAR was detectable in vivo at a median of 6 months.
Conclusions: Our study demonstrates bispecific CS1-BCMA CAR-T cells are clinical active with a good safety profile in heavily pretreated pts with MM, even after BCMA-targeted CAR-T cell therapy.
