‘Armored’ CAR T Cells Highly Active in Lymphoma After Prior CAR-T Failure

Oncology/Hematology
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Lymphoma

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81% of patients responded to CD19-targeting, IL-18-secreting therapy

by
Mike Bassett, Staff Writer, MedPage Today
May 7, 2025 • 3 min read

A next-generation, anti-CD19 enhanced CAR T-cell therapy that secretes interleukin-18 achieved a response in 81% of lymphoma patients who failed previous CAR T-cell therapy.Duration of response was 9.6 months, with some responses lasting more than 2 years.The safety profile of huCART19-IL18 was similar to that of other CAR-T products.

A next-generation, anti-CD19 enhanced (or “armored”) CAR T-cell product showed promising efficacy and safety in a phase I trial of lymphoma patients who had previously failed anti-CD19 CAR T-cell therapy.

Among 21 patients, 81% responded at 3 months after infusion of the enhanced CAR T-cell product — huCART19-IL18, which targets CD19 while secreting interleukin (IL)-18 — including complete responses in 52%. The median duration of response was 9.6 months, reported Carl June, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, and colleagues.

“Some responses were durable, now persisting beyond 2 years, and were observed in patients who had resistance to previous second-generation anti-CD19 CAR T-cell products,” the team wrote in the New England Journal of Medicine.

“These findings indicate that retargeting of CD19 with armored CAR T cells may be an effective strategy for these patients. Our trial provides proof of concept that cytokine-armored CAR T-cell treatment is feasible and may enhance antitumor activity without additional toxic effects,” they added.

Median progression-free survival was 8.7 months, and 10 patients (48%) were alive at 15 months. The safety profile of huCART19-IL1 was described as consistent with that of other CAR-T therapies.

Multiple CD19-targeting CAR T-cell therapies are approved for B-cell lymphomas, but about half of patients do not have long-term remissions with these products and are left with limited options and a poor prognosis.

“A promising strategy to improve CAR T-cell efficacy involves developing fourth-generation armored CAR T cells that secrete proinflammatory cytokines to bolster antitumor activity,” the study authors noted.

The novel therapy, huCART19-IL18, was thus designed to secrete IL-18, “a pro-inflammatory cytokine capable of enhancing the immune system, by recruiting additional immune cells to support the engineered T cells,” June explained in a press release. “In doing so, it further protects the CAR T cells and promotes their ability to attack the cancer cells.”

Moreover, huCART19-IL18 was manufactured in a 3-day process, meaning patients were able to begin CAR T-cell therapy much faster than is currently possible with available products.

For the phase I study, the researchers enrolled 28 patients from May 2021 to March 2024, 21 of whom received huCART19-IL18. Autologous T cells were obtained from the patients via leukapheresis, and bridging therapy was optional.

Most patients had subtypes of large B-cell lymphoma, including eight with diffuse large B-cell lymphoma, two with transformed follicular lymphoma, one with high-grade B-cell lymphoma, and one with T-cell histiocyte-rich B-cell lymphoma. Six patients had follicular lymphoma, and three had mantle cell lymphoma.

Patients had been heavily pretreated, with a median of seven previous therapies, and all but one had been treated with a CAR T-cell therapy approved for their lymphoma type.

Dose levels of huCART19-IL18 between 3×106 and 3×108 cells were administered as a single IV infusion 2 to 5 days after lymphodepleting chemotherapy, and a dose range of 3×106 to 7×106 of huCART19-IL18-positive cells was selected for the expansion cohort and future trials in this patient population.

As for safety, the investigators reported that cytokine release syndrome (CRS) occurred in 13 patients, with grade 3 CRS occurring in three. The median time until the onset of CRS was 4 days after infusion, and median duration was 7 days.

Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in three patients, and all three events were grade 1 or 2. The median time until the onset of ICANS was 8 days, and the median duration was 7 days.

Three patients had grade 3 infections, including COVID-19, and no secondary cancers were observed. There were no trial-related deaths nor observable differences in toxicity according to dose level.

Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

June had no disclosures. Coauthors reported various grants and personal ties to industry.

Primary Source

New England Journal of Medicine

Source Reference: Svoboda J, et al “Enhanced CAR T-cell therapy for lymphoma after previous failure” N Engl J Med 2025; DOI: 10.1056/NEJMoa2408771.