Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure.

in The New England journal of medicine by Jakub Svoboda, Daniel J Landsburg, James Gerson, Sunita D Nasta, Stefan K Barta, Elise A Chong, Michael Cook, Noelle V Frey, Joanne Shea, Amanda Cervini, Amy Marshall, Megan Four, Megan M Davis, Julie K Jadlowsky, Anne Chew, Edward Pequignot, Vanessa Gonzalez, Julia Han Noll, Luca Paruzzo, Juliana Rojas-Levine, Gabriela Plesa, John Scholler, Donald L Siegel, Bruce L Levine, David L Porter, Saba Ghassemi, Marco Ruella, Andrew Rech, Rachel M Leskowitz, Joseph A Fraietta, Wei-Ting Hwang, Elizabeth Hexner, Stephen J Schuster, Carl H June

TLDR

  • The huCART19-IL18 study demonstrated promising efficacy and a favorable safety profile in patients with relapsed or refractory lymphoma after previous anti-CD19 CAR T-cell therapy, with 81% of patients achieving a complete or partial response.

Abstract

Chimeric antigen receptor (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 to enhance antitumor activity. In this study, we assessed the safety, feasibility, and preliminary efficacy of huCART19-IL18 in patients with relapsed or refractory lymphoma after previous anti-CD19 CAR T-cell therapy. Using a 3-day manufacturing process, we administered huCART19-IL18-positive cells in doses ranging from 3×10to 3×10. A total of 21 patients received huCART19-IL18. Cytokine release syndrome occurred in 62% of the patients (47% with grade 1 or 2), and 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 detected across all dose levels. At 3 months after infusion, a complete or partial response was seen in 81% of the patients (90% confidence interval [CI], 62 to 93) and a complete response in 52% (90% CI, 33 to 71). With a median follow-up of 17.5 months (range, 3 to 34), the median duration of response was 9.6 months (90% CI, 5.5 to not reached). 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. (ClinicalTrials.gov number, NCT04684563.).

Overview

  • The study investigated the safety, feasibility, and efficacy of an anti-CD19 enhanced chimeric antigen receptor (CAR) T-cell product (huCART19-IL18) in patients with relapsed or refractory lymphoma after previous anti-CD19 CAR T-cell therapy.
  • The huCART19-IL18 product secretes interleukin-18 to enhance antitumor activity and was administered in doses ranging from 3×10^6 to 3×10^8.
  • The primary objective of the study was to evaluate the safety and efficacy of huCART19-IL18 in this patient population.

Comparative Analysis & Findings

  • The study found that huCART19-IL18 had a safety profile consistent with other CAR T-cell treatments, with cytokine release syndrome occurring in 62% of patients and immune effector-cell-associated neurotoxicity syndrome occurring in 14%.
  • Robust CAR T-cell expansion was detected across all dose levels, and at 3 months after infusion, a complete or partial response was seen in 81% of patients and a complete response in 52%.
  • The median duration of response was 9.6 months, with a range of 5.5 to not reached, and a median follow-up of 17.5 months.

Implications and Future Directions

  • The study suggests that huCART19-IL18 is a promising treatment option for patients with lymphoma who have failed previous anti-CD19 CAR T-cell therapy and may have a role in improving treatment outcomes.
  • Future studies should investigate the optimal dosing schedule and duration of treatment for huCART19-IL18 to maximize its therapeutic potential.
  • The development of huCART19-IL18 could enable the use of this treatment in combination with other therapeutic agents, potentially enhancing its efficacy and broadening its applicability.
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