Zamtocabtagene autoleucel (zamto-cel), a non-cryopreserved CAR T-cell therapy targeting both CD19 and CD20, has shown promising results in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Interim findings from the phase 2 DALY II USA study, presented at the 2025 Transplant and Cellular Therapy Meetings, indicate high response rates and manageable safety. The vein-to-vein time for this therapy is 12 to 14 days.
The DALY II USA trial (NCT04792489) enrolled adult patients with relapsed/refractory DLBCL who had received at least two prior lines of therapy. Patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide or bendamustine, followed by zamto-cel at a target dose of 2.5 x 10^6 CAR T cells/kg. The primary endpoint was overall response rate (ORR), with secondary endpoints including complete remission (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
Efficacy Outcomes
The modified intent-to-treat (mITT) population (n = 59) achieved an ORR of 72.8%, with a CR rate of 50.8% and a partial response rate of 22.0%. The median DOR was 11.4 months, and the median duration of CR was not reached. Median PFS was 9.0 months, and the 6-month PFS rate was 55%. The median OS was not reached at the time of the interim analysis.
Nirav N. Shah, MD, from the Medical College of Wisconsin, noted that many patients had high-risk disease characteristics, including elevated International Prognostic Index (IPI) scores and lactate dehydrogenase (LDH) levels. Despite these factors, the therapy demonstrated robust efficacy.
Safety Profile
The safety profile of zamto-cel was notable for its low incidence of severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). No cases of grade 3 or higher CRS were reported. Grade 3 or higher ICANS occurred in 4.3% of patients. Grade 1/2 CRS was seen in 46.4% and grade 1/2 ICANS was experienced by 17.3%. Hematologic toxicities, including neutropenia, anemia, and thrombocytopenia, were common but generally manageable.
Addressing Antigen Loss
One of the key advantages of zamto-cel is its dual targeting of CD19 and CD20, which may mitigate antigen loss as a resistance mechanism. Among patients who experienced disease progression (n = 27), only a small fraction showed loss of CD19 (7%), CD20 (7%), or both (4%). The majority (82%) showed no antigen loss.
"We need to continue to biopsy people and also to understand what is that mechanism of resistance to this dual-targeted CAR T cell product," said Shah.
Implications for DLBCL Treatment
These interim results suggest that zamto-cel is a promising therapy for relapsed/refractory DLBCL, particularly given its high response rates, manageable safety profile, and potential to overcome antigen loss. A European study is evaluating zamto-cel as a second-line treatment for transplant-ineligible patients with DLBCL in a randomized controlled setting. The outcomes of these trials could pave the way for potential FDA approval, offering a new treatment option for patients with this aggressive lymphoma.
