As of May 12, 2022, 66 pts have been enrolled, 55 have been treated with BMS-986354, and 54 were evaluable for disease response. In the dose-escalation phase (Part A), pts were treated with 20 × 106 (dose level [DL] 1, n = 7), 40 × 106 (DL2, n = 24), or 80 × 106 (DL3, n = 11) CAR+ T cells; DL2 was selected for dose expansion (Part B), and an additional 13 pts were treated. Enrolled pts had a median age of 62.5 years (range, 43–75). Median time from diagnosis was 6.2 years (range, 0.7–24.6) with a median of 5 prior regimens (range, 3–13). During dose escalation, no pts had dose-limiting toxicities (DLTs) at DL1, 4 had DLTs at DL2 (prolonged neutropenia and thrombocytopenia [n=1], prolonged neutropenia [n = 2], decreased fibrinogen [n = 1]), and 3 had DLTs at DL3 (prolonged neutropenia [n = 2], prolonged thrombocytopenia [n = 1]); all DLs were tolerable per prespecified criteria.

Cytokine release syndrome (CRS) occurred in 80.0% of all treated pts, with most experiencing grade 1 (63.6%) or grade 2 (14.5%); only 1 pt experienced ≥ grade 3 (grade 4) CRS. Median onset was day 4 (range, 2–8), median duration was 4 days (range, 1–8), and common treatments included tocilizumab (n = 38), steroids (n = 25), and anakinra (n = 9). Neurotoxicity occurred in 6 (10.9%) pts (grade 1, n = 5; grade 4, n = 1); all events resolved after a median of 2.5 days (range, 2–21). No neurotoxicity events had an onset beyond day 9. Overall, with a median follow-up of 4.9 months, the objective response rate was 98.1%, with 57.4% of pts achieving a very good partial response or better, 29.6% achieving complete response or better, and 76.4% of responses ongoing.

Compared with orva-cel, BMS-986354 drug product is less differentiated, composed primarily of naive-like and central memory CAR T cells with fewer effector and terminally differentiated CAR T cells. Following CAR stimulation, BMS-986354 led to higher antigen-specific cytokine (interferon-gamma, tumor necrosis factor alpha, and interleukin-2) production than orva-cel (Figure).

Pharmacokinetic analysis of transgene levels using droplet-digital polymerase chain reaction demonstrated robust cellular expansion across all DLs (geometric mean maximum concentration [Cmax] of 8.67 × 104 gag copies/µg, area under the curve 0 to 28 days [AUC0–28] of 85 × 104 days × gag copies/µg, median time to Cmax of 14 days at DL2). Flow cytometry analysis during dose escalation showed that similar Cmax and AUC0–28 were reached with a > 11-fold lower dose of BMS-986354 than orva-cel, demonstrating increased proliferative capacity for BMS-986354 (geometric mean Cmax of 399 cells/µL, AUC0–28 of 3674 days × cells/µL at DL2 vs Cmax of 328 cells/µL, AUC0–28 of 3890 days × cells/µL at 450 × 106 cells).