T Cells Expressing Chimeric Antigen Receptors Can Cause Anaphylaxis in Humans

Chimeric antigen receptor–expressing T cells (CAR-T cells) represent a promising, novel form of adoptive immunotherapy to overcome tolerance to cancer. Using an intermittent dosing schedule of autologous CAR-T cells electroporated with mRNA encoding a hybrid single chain molecule comprising the extracellular domain of murine monoclonal antibody against human mesothelin and the human transmembrane and cytoplasmic T-cell signaling domains, Maus and colleagues characterized and reported a serious adverse event that occurred in one of four patients receiving repeated modified T-cell infusions, with proposed modifications to address and minimize future adverse occurrence. 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 shown that transfection of T cells with 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. Because of the transient nature of CAR expression on the T cells, subjects in the clinical study were given repeated infusions of the CAR-T cells to assess their safety. One subject developed anaphylaxis and cardiac arrest within minutes of completing the third infusion. Although human anti-mouse immunoglobulin (Ig)G 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. Cancer Immunol Res; 1(1); 26–31. ©2013 AACR.