Synthetic Binding Domain CAR T Therapy Yields 100% ORR in R/R Multiple Myeloma


69% of patients followed up for at least 1 year continue to have an ongoing response.

CART-ddBCMA, an autologous anti-BCMA chimeric antigen receptor (CAR) T-cell therapy using the novel, synthetic binding D-Domain, has demonstrated clinical activity in relapsed/refractory multiple myeloma, according to new data from a phase 1 study (NCT04155749).

These data were presented at the 2022 American Society of Clinical Oncology (ASCO) meeting, held June 3-7, 2022, held both virtually and in Chicago, Illinoisby Matthew J. Frigault, MD, instructor, medicine, Harvard Medical School, and clinical director, cellular immunotherapy program, BMT & cellular therapy, Massachusetts General Hospital.

“CART-ddBCMA contains a novel D domain that was computationally designed. It’s comprised of 3 alpha helices that you can mutate the binding surface to get different degrees and characteristics of affinity as well as immunogenicity... Importantly, D domains are actually significantly smaller than traditional T-cell receptor (TCR)-based therapies, single chain-based therapies, or camelid-based therapies... They’re extremely stable at high temperatures and rapidly fold,” Frigault said during his presentation.

The multi-center, open-label study has treated 25 patients with a median age of 66 years (range, 44-76) with 100x106 CART-ddBCMA cells (cohort 1) and 6 patients with a median age of 60 years (range, 52-65) with 300x106 cells (cohort 2). Patients in cohort 1 had a median of 5 prior lines of therapy (range, 3-16) and 9 (36%) had extramedullary disease (EMD). Patients in cohort 2 had a median of 4 prior lines of therapy (range, 3-16) and 3 (50%) had EMD. Prior to dosing, patients received fludarabine and cyclophosphamide (30/300 mg/m2/day) for 3 days.

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Patients were followed up for a median of 9.8 months (range, 2-23.7). Of 16 patients with a minimum follow-up of 12 months and median follow-up of 17.7 months, ORR was 100% and complete response (CR) rate was 81% (n = 13). Eleven patients (69%) continue to have an ongoing response. In 24 patients followed up for at least 6 months, median follow-up was 13.3 months, ORR was 100%, CR rate was 79%, and 22 patients (92%) have an ongoing response. In all 31 patients followed up for at least 1 month, median follow-up was 12.1 months, ORR was 100% and CR rate was 71%.

Overall, very good partial response (VGPR) rate was 88%. Seventeen of 20 (85%) evaluable patients have achieved best minimal residual disease response of ≥10-5. Median duration of response, progression free survival and overall survival are not yet evaluable.

CART-ddBCMA was well-tolerated, with standard cases of neutropenia, anemia, thrombocytopenia, and lymphocytopenia. All patients experienced ctokine release syndrome (CRS) but only 1 case at dose level 2 was grade 3. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4 patients, 2 at grade 2 or lower and 2 at grade 3 (1 in each dose level). CRS and ICANS resolved within 30 days without sequelae with standard management.

“We examined 2 dose levels and did not reach our maximum tolerated dose. We had high T cell viability and low interpatient variability in our cell manufacturing process. Overall, the AE profile was very positive. We didn’t see any tissue targeted toxicities observed... We had no cases of grade 3 or higher CRS in our dose level 1. We’re excited to begin enrolling the pivotal phase 2 hopefully by the end of this year,” Frigault said.

Frigault MJ, Rosenblatt J, Cook D, et al. Phase 1 study of CART-ddBCMA in relapsed or refractory multiple myeloma. Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022. Abstract # 8003.
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