T Cells Expressing Chimeric Antigen Receptors Can Cause Anaphylaxis in Humans

TLDR

CAR‑T cells engineered with mRNA can transiently express chimeric antigen receptors, offering antitumor efficacy while allowing safety assessment of new targets, though anti‑mouse IgG responses have been reported without known clinical consequences. The study aimed to evaluate the safety of autologous mRNA‑CAR T cells targeting mesothelin in four patients. Patients received repeated infusions of electroporated mRNA‑CAR T cells to compensate for transient CAR expression and evaluate safety. One patient experienced anaphylaxis and cardiac arrest minutes after the third infusion, marking the first clinical report of CAR‑T‑cell–induced anaphylaxis likely mediated by IgE against the murine CAR, underscoring immunogenicity risks with intermittent dosing.

Abstract

T cells can be redirected to overcome tolerance to cancer by engineering with integrating vectors to express a chimeric antigen receptor (CAR). In preclinical models, we have previously demonstrated that transfection of T cells with messenger RNA (mRNA) coding for a CAR is an alternative strategy that has antitumor efficacy and the potential to evaluate the on-target off-tumor toxicity of new CAR targets safely due to transient mRNA CAR expression. Here, we report the safety observed in four patients treated with autologous T cells that had been electroporated with mRNA coding for a CAR derived from a murine antibody to human mesothelin. Due to the transient nature of CAR expression on the T cells, subjects in the clinical study were given repeated infusions of the CAR-T cells in order to assess their safety. One subject developed anaphylaxis and cardiac arrest within minutes of completing the 3rd infusion. Although human anti-mouse IgG antibodies have been known to develop with CAR-transduced T cells, they have been thought to have no adverse clinical consequences. This is the first description of clinical anaphylaxis resulting from CAR-modified T cells, most likely through IgE antibodies specific to the CAR. These results indicate that the potential immunogenicity of CARs derived from murine antibodies may be a safety issue for mRNA CARs, especially when administered using an intermittent dosing schedule.