Cardiovascular toxicity and titin cross-reactivity of affinity enhanced T cells in myeloma and melanoma
Menée sur deux patients atteints d'un myélome ou d'un mélanome, cette étude met en évidence de graves effets cardiovasculaires indésirables, non prédits par les études précliniques, induits par une immunothérapie à base de lymphocytes T modifiés
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).