A non-cryopreserved, rapidly delivered tandem CAR-T cell therapy, zamtocabtagene autoleucel (zamto-cel, Miltenyi Biomedicine), has shown promising results in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Interim results from the phase 2 DALY II USA trial, presented at the ASH Annual Meeting and Exposition, demonstrated a 75% overall response rate (ORR) among treated patients.
Key Findings from the DALY II USA Trial
The DALY II USA trial evaluated zamto-cel, an autologous tandem CD20-CD19-directed CAR-T therapy, in adults with relapsed or refractory DLBCL who had received at least two prior therapies. The interim analysis included 69 patients, with 59 having at least 3 months of follow-up. Patients received a single dose of zamto-cel (2.5 x 106 CAR T cells/kg) on day 0.
The primary endpoint was ORR, defined as the best overall response of either complete or partial response. Secondary endpoints included complete response rate, duration of response, progression-free survival (PFS), overall survival (OS), safety, and expression of CD19 and CD20 antigens at relapse.
Efficacy and Safety Results
The study reported a 72.8% ORR (95% CI, 59.7-83.6) and a 50.8% complete response rate (95% CI, 35.9-62.5). Six-month PFS was 55% (95% CI, 41-67), 12-month PFS was 42% (95% CI, 28-56), and 12-month OS was 72% (95% CI, 57-83). The median PFS was 9 months, and the median response duration was 11.4 months. The median duration was not reached for those who had a complete response.
Regarding safety, 46.4% of patients developed cytokine release syndrome (CRS), with all cases being grade 1 or 2. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 17.4% of patients (75% grade 1 or 2; 4.3% grade 3). One patient developed immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, which resolved after 2 days.
Advantages of Non-Cryopreserved CAR-T
According to Nirav N. Shah, MD, MSHP, associate professor of medicine at Medical College of Wisconsin, the non-cryopreserved nature of zamto-cel offers several advantages. A fresh formula has better kinetics and expansion compared to cryopreserved therapies. The vein-to-vein time is approximately 14 days, reducing the number of patients who drop off due to delays in receiving the product.
Future Directions
Researchers are continuing long-term follow-up and are working to develop zamto-cel for other B-cell malignancies. The closed-production system used in manufacturing allows for rapid scalability and potential global accessibility. Zamtocabtagene autoleucel is also being investigated as a second-line treatment for DLBCL in Europe.
Shah noted that the trial is nearing its planned accrual of 100 patients and emphasized the favorable outcomes and safety profile observed in this multicenter trial of tandem-targeting CAR-T therapy.
