T cells expressing chimeric antigen receptors can cause anaphylaxis in humans.
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.
Authors' Affiliations: Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Marcela V
MV
Maus
Andrew R
AR
Haas
Gregory L
GL
Beatty
Steven M
SM
Albelda
Bruce L
BL
Levine
Xiaojun
X
Liu
Yangbing
Y
Zhao
Michael
M
Kalos
Carl H
CH
June
D000369:Aged, 80 and over; D000707:Anaphylaxis / Q000209:etiology* / Q000276:immunology; D000818:Animals; D046528:Chimerism; D057176:Compassionate Use Trials; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000009:adverse effects* / Q000379:methods*; D008297:Male; D000090204:Mesothelin; D008654:Mesothelioma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D010997:Pleural Neoplasms / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D058851:GPI-Linked Proteins; D007128:Immunoglobulin Fragments; C000715528:Msln protein, mouse; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D000090204:Mesothelin