Portal de Periódicos da CAPES

T Cells Expressing Chimeric Antigen Receptors Can Cause Anaphylaxis in Humans

2013; American Association for Cancer Research; Volume: 1; Issue: 1 Linguagem: Inglês

10.1158/2326-6066.cir-13-0006

2326-6074

Marcela V. Maus, Andrew R. Haas, Gregory L. Beatty, Steven Μ. Albelda, Bruce L. Levine, Xiaojun Liu, Yangbing Zhao, Michael Kalos, Carl H. June,

T-cell and B-cell Immunology

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.