Safety and promising efficacy with enhanced CAR T-cell therapy for lymphoma

Abstract

Results of the first-in-human trial using enhanced chimeric antigen receptor (CAR) T-cell therapy, armed with proinflammatory cytokines (interleukin 18 [IL-18]) to target malignant lymphocytes in patients with refractory or relapsed lymphoma, show that the enhanced CAR T-cell therapy carries a safety profile similar to that of other CAR T-cell therapies and demonstrates promising efficacy.¹

Of the 21 patients in the trial, 81% achieved a complete or partial response after 3 months of the armored CAR T-cell therapy, with 52% achieving a complete response. In the same group of participants, 62% had cytokine release syndrome (47% of these cases were grade 1 or 2), and 14% had grade 1 or 2 immune effector cell-associated neurotoxicity syndrome. The median duration of response was 9.6 months at a median follow-up of 17.5 months.

Toxicity was similar to that of other CAR T-cell therapies and consisted mainly of grade 1 or 2 adverse events, none of which were unexpected or delayed.

The lead author of the study, Jakub Svoboda, MD, an associate professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania, says that he and his colleagues are encouraged by the favorable toxicity profile of the armored CAR T-cell therapy and “surprised by the efficacy in this setting with over 50% of patients achieving complete response.”

Preclinical studies conducted by the researchers demonstrated that IL-18–armored CAR T cells have superior antitumor efficacy and result in prolonged survival in mouse models. Dr Svoboda and his colleagues decided to test their armored CAR T-cell therapy on patients with lymphoma who had relapsed after therapy or did not respond to standard anti-CD19 CAR T-cell therapy.

Dr Svoboda says that the trial demonstrated that it is possible to retarget the same surface antigen (CD19) with armored CAR T cells and achieve durable responses. He underscores that approximately one third of the patients had no response to prior standard anti-CD19 CAR T-cell therapy. Some of these refractory patients achieved long-term responses when they were treated with the armored anti-CD19 CAR T-cell therapy.

However, he cautions that the results of the trial come from a small sample. He and his colleagues are currently conducting a larger trial using IL-18–armored anti-CD19 CAR T-cell therapy to confirm the efficacy results. He says that the concept of administering CAR T-cell therapy after the failure of prior CAR T-cell therapy is a reasonable strategy with the right product.

“We are hoping that the concept of armoring CARs with proinflammatory cytokines may have implications in settings where cellular therapies face challenges,” he says, adding that secreting cytokines at the tumor site may allow for the recruitment of important components of the immune system and enhance the CARs themselves.

“This modification may ultimately overcome some of the immunosuppressive effects of the tumor microenvironment, which could be highly relevant in the treatment of solid malignancies,” he says.