T cells expressing chimeric antigen receptors can cause anaphylaxis in humans

• Published in: Cancer immunology research Vol. 1; no. 1; p. 26
• Main Authors: Maus, Marcela V, Haas, Andrew R, Beatty, Gregory L, Albelda, Steven M, Levine, Bruce L, Liu, Xiaojun, Zhao, Yangbing, Kalos, Michael, June, Carl H
• Format: Journal Article
• Language: English
• Published: United States 01-07-2013
• Subjects: Aged, 80 and over; Anaphylaxis - etiology; Anaphylaxis - immunology; Animals; Chimerism; Compassionate Use Trials; GPI-Linked Proteins - genetics; GPI-Linked Proteins - immunology; Humans; Immunoglobulin Fragments - biosynthesis; Immunoglobulin Fragments - genetics; Immunoglobulin Fragments - immunology; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Male; Mesothelin; Mesothelioma - immunology; Mesothelioma - therapy; Mice; Pleural Neoplasms - immunology; Pleural Neoplasms - therapy; Receptors, Antigen, T-Cell - biosynthesis; Receptors, Antigen, T-Cell - immunology; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; T-Lymphocytes - immunology
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-13-0006

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.