Tandem non-cryopreserved CAR-T exhibits ‘favorable’ activity in advanced DLBCL
Key takeaways:
- Most patients in a phase 2 trial responded to a non-cryopreserved tandem CAR-T.
- Most trial participants received the therapy within 14 days, the standard production and delivery time for zamto-cel.
SAN DIEGO — A rapidly delivered tandem chimeric antigen receptor T-cell therapy produced favorable outcomes for patients with relapsed or refractory diffuse large B-cell lymphoma, according to interim results of a phase 2 trial.
About 75% of patients who received zamtocabtagene autoleucel (Miltenyi Biomedicine) responded to therapy, findings presented at ASH Annual Meeting and Exposition showed. Nearly all participants in the DALY II USA trial received the noncryopreserved product within 2 weeks, the standard production and delivery time for zamtocabtagene autoleucel.
“We’re really pleased,” Nirav N. Shah, MD, MSHP, associate professor of medicine at Medical College of Wisconsin, told Healio. “It’s tandem targeting. It’s a fresh infusion. It’s a rapid turnaround. There’s a lot of different advantages that makes this product viable for patients.”
Background and methods
Zamtocabtagene autoleucel, often called zamto-cel, is an autologous tandem CD20-CD19-directed CAR-T,
Researchers previously evaluated the agent. They found a fresh formula had “better kinetics with better expansion” compared with a cryopreserved therapy, Shah said.
“The other advantage of a noncryopreserved infusion is that you’re able to get the product to the patient more quickly,” he added. “Lymphodepletion starts during manufacturing, and this is really a true vein-to-vein time of 14 days. Fewer patients fall off because they can get the product in a timely manner.”
DALY II USA included adults with relapsed or refractory DLBCL who had received at least two prior therapies.
Within this interim analysis, researchers had administered zamto-cel to 69 patients (median age, 65 years; range, 25-85; 68.1% men; 82.6% white). Of those, 59 (median age, 65 years; range, 25-85; 68% men) had at least 3 months of follow-up.
Patients received one dose of zamto-cel (2.5 x 106 CAR T cells/kg) on day 0.
Overall response rate — defined as best overall response of either complete or partial response — served as the primary endpoint. Complete response rate, duration of response, PFS, OS, safety, and expression of CD19 and CD20 antigens at relapse served as secondary endpoints.
Results and next steps
Researchers successfully manufactured the CAR-T for 91.3% of patients. Four patients received a cryopreserved CAR-T due to patient related factors.
The final product had a mean viability of 96%, including a 29.4% transduction efficiency.
Results showed an ORR of 72.8% (95% CI, 59.7-83.6) and a 50.8% (95% CI, 35.9-62.5) complete response rate.
Researchers observed 6-month PFS of 55% (95% CI, 41-67), 12-month PFS of 42% (95% CI, 28-56) and a 12-month OS of 72% (95% CI, 57-83).
Investigators reported median PFS of 9 months and median response duration of 11.4 months. Those who had a complete response did not reach a median duration.
Safety analyses showed 46.4% of trial participants developed cytokine release syndrome — all cases were grade 1 or grade 2 — and 17.4% developed immune effector cell-associated neurotoxicity syndrome (75% grade 1 or grade 2; 4.3% grade 3).
A single participant developed immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome that resolved after 2 days.
Of 27 patients who had biopsies following progression, two had CD19-negative relapse, two had CD20-negative relapse, and one person experienced both.
“This is the first large multicenter trial with tandem-targeting, and the only one I’m aware of that is delivering fresh cells in a multicenter fashion,” Shah said. “We were able to successfully do this with really favorable outcomes and impeccable safety.”
Researchers have nearly reached their planned accrual of 100 patients, Shah said.
Long-term follow-up will continue.
Shah and colleagues are working to develop zamto-cel for other B-cell malignancies, as well.
“There’s potential to globalize this product because the manufacturing uses this closed-production system, which is really something you can build up quickly compared with some of the large manufacturing facilities that currently exist,” Shah said.
Zamto-cel is being investigated as a second-line treatment for DLBCL in Europe, Shah added.
“This is built on the premise of a fresh product with cryopreservation as a backup, in case a patient complication happens or something makes it challenging for them to get a fresh product,” he said. “Other groups are launching their products with the idea of using a fresh infusion. I do think there's a wave coming of people doing this sort of work.”
For more information:
Nirav N. Shah, MD, can be reached at nishah@mcw.edu.
Perspective
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Bispecific CAR-T products, including CD20/CD19- and CD22/CD19- directed, now aim to fill this unmet need to build on the success of approved products. So far, clinical trials with numerous bispecific CAR constructs remain ongoing without a clear answer as to the optimal therapy.
Efficacy and persistence of fresh vs. cryopreserved products has also been an area of investigation, as the impact of cryopreservation was not well studied in initial trials of commercial products due to feasibility constraints. Though some evidence of increased apoptosis signaling among other changes in cryo-thawed CAR-Ts has suggested that fresh CAR-T products may produce higher rates of clinical response, this has not yet been shown to be the case.
These phase 2 interim results mark another important step in understanding new developments in CAR-T therapy. Treatment with zamto-cel appears to demonstrate an acceptable safety profile, with low incidence of grade 3 treatment-emergent adverse events. Response rates are similar to existing products, with an ORR of 73% and complete response rate of 49%. Biopsies collected at progression for available patients demonstrated overall lower rates of antigen loss compared with those typically seen with monospecific CD19-directed CAR-T, an important contributor to relapse among these patients. Once fully accrued, the final results from this study are likely to provide more important guidance regarding efficacy of bispecific CAR-T products.
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Shah NN, et al. Abstract 68. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2024; San Diego.
