In a single-center phase I trial reported in The New England Journal of Medicine, Svoboda et al assessed the safety, feasibility, and preliminary efficacy of an enhanced chimeric antigen receptor (CAR) T-cell therapy (huCART19-IL18) in patients with relapsed or refractory lymphoma after previous anti-CD19 CAR T-cell therapy.
As stated by the investigators, “…CAR T cells targeting CD19 have transformed the treatment of B-cell cancers, but many patients do not have long-term remission. We designed an anti-CD19 enhanced (armored) CAR T-cell product (huCART19-IL18) that secretes interleukin-18 (IL-18) to enhance antitumor activity.”
Study Details
In the trial, 21 evaluable patients enrolled at the University of Pennsylvania between May 2021 and March 2024 received huCART19-IL18-positive cells at doses of 3×106 to 3×108 in a single infusion 2 to 5 days after lymphodepleting chemotherapy. 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 had follicular lymphoma; and three had mantle-cell lymphoma.
Key Findings
Cytokine-release syndrome occurred in 62% of patients and was grade 3 (no grade 4 or 5 events) in three patients (14%). Immune effector-cell–associated neurotoxicity syndrome occurred in 14% (all grade 1 or 2). No unexpected adverse events were observed.
Robust CAR T-cell expansion was observed across all dose levels. At 3 months after infusion, complete or partial response was observed in 81% of patients (90% confidence interval [CI] = 62%–93%), with complete response in 52% (90% CI = 33%–71%). At a median follow-up of 17.5 months (range = 3–34 months), median duration of response was 9.6 months (90% CI = 5.5 months to not reached). Objective responses were observed across all lymphoma subtypes, including 67% of patients with large B-cell lymphoma, 100% of those with follicular lymphoma, and 100% of those with mantle cell lymphoma.
The investigators concluded: “In this small study, huCART19-IL18 had a safety profile consistent with other CAR T-cell treatments and showed promising efficacy at low cell doses in patients with lymphoma after the failure of previous anti-CD19 CAR T-cell therapy.”
Jakub Svoboda, MD, of the Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, and Carl H. June, MD, of the Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, are the corresponding authors for the New England Journal of Medicine article.
Disclosure: The trial was supported by the National Cancer Institute. For full disclosures of all study authors, visit www.nejm.org.
