1. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma
- Author
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Linette, Gerald P., Stadtmauer, Edward A., Maus, Marcela V., Rapoport, Aaron P., Levine, Bruce L., Emery, Lyndsey, Litzky, Leslie, Bagg, Adam, Carreno, Beatriz M., Cimino, Patrick J., Binder-Scholl, Gwendolyn K., Smethurst, Dominic P., Gerry, Andrew B., Pumphrey, Nick J., Bennett, Alan D., Brewer, Joanna E., Dukes, Joseph, Harper, Jane, Tayton-Martin, Helen K., Jakobsen, Bent K., Hassan, Namir J., Kalos, Michael, and June, Carl H.
- Abstract
An obstacle to cancer immunotherapy has been that the affinity of T-cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01–restricted MAGE-A3. Open-label protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T-cell infusion, events not predicted by preclinical studies of the high-affinity TCRs. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed T-cell infiltration. No MAGE-A3 expression was detected in heart autopsy tissues. Robust proliferation of the engineered T cells in vivo was documented in both patients. A beating cardiomyocyte culture generated from induced pluripotent stem cells triggered T-cell killing, which was due to recognition of an unrelated peptide derived from the striated muscle-specific protein titin. These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs.
- Published
- 2013
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