Engineered T cell receptors can have redundant recognition of alternative protein motifs, resulting in severe cardiac toxicity.
The use of induced pleuripotent stem cells (iPSC) is a promising approach to identify potential off target effects of engineered T cells
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 T cell receptor against HLA-A*01-restricted MAGE-A3. Open-labeled 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 pre-clinical studies of the high-affinity T cell receptors (TCR). 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 cases 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. The protocols were registered at clinicaltrials.gov (NCT01350401 and NCT01352286).
- Submitted March 15, 2013.
- Accepted June 6, 2013.
- Copyright © 2005 American Society of Hematology