KEY TAKEAWAYS
- The phase 1 study assessed the responses of HuCART19-IL18 in patients with R/R NHL who have previously failed anti-CD19 CART therapy.
- The trial explored various doses of huCART19-IL18 (ranging from 3 to 300 million cells) administered as a single IV infusion after lymphodepleting chemotherapy.
- This ongoing trial demonstrated encouraging safety and efficacy results observed in the early stages of the clinical trial.
The first-in-human trial of huCART19-IL18 enrolled individuals aged 18 and above with CD19+ relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL), who have undergone a minimum of two prior lines of treatment, including the lack of response to previous chimeric antigen receptor T-cell (CART) therapy. The study employed a modified Bayesian optimal interval dose titration design and explored a dosage range from 3 to 300 million huCART19-IL18+ cells. The product was given as a single IV infusion following lymphodepleting (LD) chemo. Incorporating bridging therapy was discretionary, and re-treatment with huCART19-IL18 was permissible for patients (pts) who did not attain a complete response (CR). The responses were evaluated at 3, 6, 9, and 12 months using the Lugano criteria for NHL and the revised iwCLL criteria for CLL.
As of March 3, 2023, 16 pts have been enrolled in the study. Among them, 15 pts had the huCART19-IL18 manufactured and acquired the minimum dose outlined in the protocol. Of the 13 pts who have received the infusion, includes 5 with diffuse large B-cell lymphoma (DLBCL), 4 with follicular lymphoma (FL), 2 with mantle cell lymphoma (MCL), 1 with high-grade B-cell lymphoma (HGBCL), and 1 with T-cell/histiocyte-rich large B-cell lymphoma (THRBCL). The median age is 65 years, ranging from 53 to 74, with a majority (77%) male. Notably, 92% of them had prior anti-CD19 CART (axi-cel 6, tisa-cel 4, brex-cel 1, tisa-cel+liso-cel 1), with 67% experiencing a relapse after prior CART therapy, while 33% were refractory to it. The median number of prior treatments was 8 (4–14); 11 (85%) pts administered bridging therapy.LD chemo was administered to 92% of the pts. Three pts were treated at DL1 (3 × 106 CART+ cells), two at DL2 (7 × 106), one at a dose between DL2-3 (2.8 × 107), six at DL3 (3 × 107), and one at DL4 (7 × 107). Two patients underwent re-treatment, one at DL1 and the other at DL3. Out of the 12 pts evaluated for safety, there were no study-related deaths.
The most prevalent potentially related non-hematologic Grade 3/4 toxicities were infection (17%), CRS-associated hypoxia (17%), and hypotension (17%). CRS was observed in 7 pts (58%), with its severity categorized as Grade 1 in 4 pts, Grade 2 in 2 pts, and Grade 3 in 1 patient. Additionally, ICANS was detected in 2 pts (17%), with Grade 1 in 1 patient and Grade 2 in 2 pts. These effects were transient and reversible, with three patients (25%) necessitating tocilizumab for management. Out of the 11 pts evaluated for efficacy, the three-month overall response rate was 82% (90% CI: 53–97), while the complete response rate was 55% (90% CI: 27–80). One patient who exhibited a partial response at the three-month mark achieved a sustained complete response after re-treatment with huCART-IL18. At a median follow-up of 12 mos (ranging from 3 to 20) for the eligible pts the responses have proven to be enduring, with the median duration not being reached and all pts are alive. Ongoing investigations are focused on correlative analyses concerning CART expansion/persistence and cytokine levels.
The administration of HuCART19-IL18 treatment led to durable responses in pts with CD19+ NHL who are R/R to previous second-generation anti-CD19 CART therapies. The trial is ongoing at the DL4 dosage level, and a protocol amendment has been implemented to include CD19+ B-cell acute lymphoblastic leukemia (B-ALL) pts.
Source: https://onlinelibrary.wiley.com/doi/10.1002/hon.3163_6
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT04684563
Svoboda, J., Landsburg, D. L., Chong, E. A., Barta, S. K., Nasta, S. D., Ruella, M., Hexner, E. O., Marshall, A., Leskowitz, R., Four, M., Shea, J., Cervini, A., Davis, M. M., Please, G., Hasenmayer, D., Amortegui, J. R., Hwang, W., Frey, N., Siegel, D. L., Fraietta, J., Levine, B., Porter, D. L., Schuster, S. J., June, C. H. FOURTH GENERATION HUCART19-IL18 PRODUCES DURABLE RESPONSES IN LYMPHOMA PATIENTS PREVIOUSLY RELAPSED/REFRACTORY TO ANTI-CD19 CAR T-CELL THERAPY https://onlinelibrary.wiley.com/doi/10.1002/hon.3163_6
