Josh Friedman , 2025-05-12 18:54:00
Key takeaways:
- Tandem-target CAR-T produced a response in all participants with relapsed or refractory mantle cell lymphoma in a phase 1/2 study.
- Patients received their CAR-T within 8 to 12 days of lymphodepletion.
A rapidly developed, dual-target chimeric antigen receptor T-cell therapy produced a 100% overall response rate in patients with relapsed or refractory mantle cell lymphoma in a phase 1/2 study.
In all, 88% of participants achieved a complete response with CD20-CD19-directed therapy.
Additionally, every patient received their treatment within 8 to 12 days of starting lymphodepletion.
Nirav N. Shah
“Dual targeting in mantle cell lymphoma, a disease characterized by bright CD20 expression, may have potential benefits based on this clinical trial,” Nirav N. Shah, MD, MSHP, associate professor of medicine at Medical College of Wisconsin, told Healio. “We’re excited to learn more by expanding on this single center clinical trial with an ongoing multicenter trial that’s actively enrolling in [the trial].”
‘CD20 bright lymphoma’
Patients diagnosed with mantle cell lymphoma have a 5-year relative survival rate of 55.6%, according to data from City of Hope.
Two CD19 CAR-T therapies have garnered approval for treatment — brexucabtagene autoleucel (Tecartus, Kite Pharma/Gilead Sciences) and lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb).
However, approximately 15% of patients who receive brexucabtagene autoleucel develop grade 3 or worse cytokine-release syndrome (CRS) and 31% develop grade 3 or worse immune effector cell-associated neurotoxicity syndrome (ICANS), according to study background.
Lisocabtagene maraleucel causes fewer adverse events, but patients have a lower response rate than brexucabtagene autoleucel and a PFS of only 15.3 months.
“Biologically, mantle cell is a CD20 bright lymphoma, leading us to hypothesize that targeting both CD19, which we know is an effective target in CAR-T, and CD20, which is effectively harnessed with other types of drugs, could lead to better outcomes,” Shah said.
Healio previously reported that zamtocabtagene autoleucel (Miltenyi Biomedicine), also called zamto-cel which is the same construct as utilized in [the current] study, produced a 72.8% overall response rate for patients with relapsed or refractory diffuse large B-cell lymphoma in the DALY II USA Trial.
This trial performed as a single center study focused only on patients with mantle cell lymphoma who had failed two previous lines of therapy or relapsed after transplant.
The trial included 17 patients (median age, 63 years; range 50-74; 88% men; median lines of prior therapy, four; range, two-eight). The phase I safety portion of the trial included three patients, and the phase 2 single-arm section had 14.
Patients began lymphodepletion and then received one dose of 20.19 CAR-T cells (a product with the same construct as zamto-cel and at the same dose 2.5 x 106 CAR T cells/kg once produced). Researchers reported a manufacturing process of 8 to 12 days.
The primary endpoint was the 3-month CR rate. Overall response rate, complete response rate, minimal residual disease, duration of remission, safety outcomes, PFS and OS served as secondary endpoints.
‘We were pleased’
Participants had an ORR of 100%, with a best complete response rate of 88%.
Patients in the phase 2 cohort had a complete response rate of 86% on day 90.
Overall, two patients relapsed, one at 8 months and another at 24 months.
At median follow-up of 15.8 months, median PFS, duration of response and OS did not get reached.
Participants had a 1-year PFS of 80% (95% CI, 49%-93%), 1-year duration of response of 93% (95% CI, 61%-99%) and 1-year OS of 86% (95% CI, 55%-96%).
Of 14 evaluable patients, 79% had no minimal residual disease at median follow-up of 96 days (range, 85-258).
“We were pleased,” Shah said.
Nearly all participants (94%) developed grade 1 or 2 CRS. None developed grade 3 or worse disease.
Any-grade ICANS occurred in 18% of patients, and grade 3 events developed in 12%. Clinicians resolved the grade 3 ICANS.
“I would say that the toxicity profile of this is similar to lisocabtagene maraleucel,” Shah said.
In all, three patients died of non-relapse events related to infectious complications.
‘Any malignancy in lymphoma’
A multicenter, phase 2 investigation is ongoing.
Researchers want to accrue approximately 70 patients with mantle cell lymphoma within a year as part of this multicenter study, Shah said.
“We still don’t have a good understanding as to why CAR-T was so successful in some, and why others relapsed,” Shah said. “The other big thing is [that] this looks good in a single-center study. We’re very experienced with this CAR-T and so it is important to evaluate in a multicenter fashion, which we have initiated as part of the DALY II USA clinical trial.. How will this CAR-T develop and evolve as we disperse it?”
Future research may involve first-line trials and evaluation in other diseases.
“We have previously presented data in chronic lymphocytic leukemia,” Shah said. “We’ve had some really nice outcomes, but that data are still maturing. By targeting CD20 and CD19, you really open yourself up to almost any malignancy in lymphoma. CD20 is the most ubiquitous target out there in lymphoma. You see it in marginal zone lymphoma, follicular lymphoma, CLL, mantle cell and diffuse large B cell lymphoma.
“We focused initially on DLBCL and mantle because those are ones where there’s a clear clinical indication for CAR-T, but we hope to continue to develop this for other B cell malignancies, as well.”
References:
For more information:
Nirav N. Shah, MD, MSHP, can be reached at nishah@mcw.edu.
Sources/Disclosures
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Disclosures:
Miltenyi Biomedicine supported this study. Shah reports stock and ownership interests in Tundra Targeted Therapeutics; consulting or advisory roles for AbbVie, BeiGene, Cargo Therapeutics, Galapagos NV, Incyte, Janssen Oncology, Juno/Bristol Myers Squibb, Kite, Loxo/Lilly, Novartis and Seagen; research funding from Adaptive Biotechnologies, Genentech, Loxo/Lilly and Miltenyi Biotec; and travel, accommodations and/or expenses from Loxo/Lilly and Miltenyi Biomedicine. Please see the study for all other authors’ relevant financial disclosures.
