Safety and efficacy of armored huCART19-IL18 in patients with relapsed/refractory lymphomas that progressed after anti-CD19 CAR T cells.
Jakub Svoboda, Daniel J. Landsburg, Sunita D. Nasta, Stefan K. Barta, Elise A. Chong, Michael J. LaRiviere, Joanne Shea, Amanda Cervini, Elizabeth O. Hexner, Amy Marshall, Megan Four, Rachel Leskowitz, Megan M. Davis, Wei‐Ting Hwang, Noelle V. Frey, Donald L. Siegel, Joseph A. Fraietta, David Porter, Stephen J. Schuster, Carl H. June
Abstract
7004 Background: A substantial proportion of patients (pts) with relapsed/refractory (R/R) non-Hodgkin lymphomas (NHL) will not derive a long-term benefit from the existing anti-CD19 chimeric antigen receptor (CAR) T cells. To enhance therapeutic efficacy, we have engineered huCART19-IL18, a 4 th generation 4-1BB anti-CD19 construct, armored with the ability to secrete the pro-inflammatory cytokine, IL-18. Methods: This is a first-in-human trial using huCART19-IL18 for CD19+ B-cell malignancies (NCT04684563). Expedited 3-day manufacturing is utilized to limit T-cell exhaustion. To be eligible for the NHL cohort, pts must be R/R to prior anti-CD19 CAR T cells if indicated by FDA label. Dose levels (DL) between 3x10 6 and 3x10 8 of huCART19-IL18+ cells are administered as a single IV infusion following lymphodepleting chemotherapy. Bridging therapy is optional. Responses are first assessed at 3 months (mo) using Lugano criteria. Results: As of January 20, 2024, 21 pts with CD19+ NHL were infused with huCART19-IL18. Characteristics include median age 64 yrs (47-74), 76% male, 9 (43%) DLBCL, 6 (29%) FL, 3 (14%) MCL, 2 (10%) tFL, 1 (5%) HGBCL. Median number of prior Rx was 7 (4-14) with 20 (95%) pts R/R to prior anti-CD19 CAR T cells. Manufacturing of DL5 (3x10 8 ) was not feasible due to inability to achieve the target dose in 4/6 (67%) pts assigned to DL5. 18 (86%) pts received bridging. 3 pts received DL1 (3x10 6 ), 4 pts DL2 (7x10 6 ), 1 pt non-defined dose (2.8x10 7 ), 6 pts DL3 (3x10 7 ), 5 pts DL4 (7x10 7 ), 2 pts DL5 (3x10 8 ). No study-related deaths occurred in 21 safety-evaluable pts. CRS occurred in 15 (71%) pts: G1 in 8 (38%), G2 in 4 (19%), G3 in 3 (14%). ICANS occurred in 3 (14%) pts: G1 in 2 (10%), G2 in 1 (5%). The most common G3 adverse events at least possibly related to huCART19-IL18 included fatigue (38%), hypotension (29%), and low fibrinogen (23%). 20 pts are efficacy evaluable with median (m) follow-up of 15 mo (3-31). The 3 mo ORR was 80% (90% CI: 60-93%), with CR 50% (90% CI: 30-70%) and PR 30% (90% CI: 14-51%). mDOR was 10 mo (5.5-NR). mPFS was 8.7 mo (90% CI 5-NR), and mOS was NR (90% CI 25 mo-NR). We detected continued persistence of huCART19-IL18 in pts with 24 mo follow-up. No correlation between cell dose and outcome was identified, but response rates and mean expansion (copies/µg gDNA) were higher in pts previously exposed to CD28 CAR than those who had prior 4-1BB CAR (Table). Conclusions: Treatment with huCART19-IL18 has an acceptable safety profile and produced durable remissions in heavily pre-treated pts with R/R NHL despite prior CAR T-cell therapy. The subtype of the preceding CAR product may influence the expansion and effectiveness of huCART19-IL18. Clinical trial information: NCT04684563 . [Table: see text]