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Blood ; 122(6): 863-71, 2013 Aug 08.
Article in English | MEDLINE | ID: mdl-23770775

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.


Subject(s)
Cardiovascular Diseases/complications , Melanoma/blood , Multiple Myeloma/blood , Muscle Proteins/metabolism , Myocardium/pathology , Protein Kinases/metabolism , T-Lymphocytes/cytology , Alleles , Amino Acid Motifs , Antigens, Neoplasm/metabolism , Cell Culture Techniques , Connectin , Cytokines/metabolism , Epitopes/metabolism , HLA-A Antigens/metabolism , Humans , Immunotherapy, Adoptive , Induced Pluripotent Stem Cells/cytology , Male , Melanoma/therapy , Middle Aged , Multiple Myeloma/therapy , Myocardium/immunology , Neoplasm Proteins/metabolism , Peptides/metabolism , Protein Engineering , Receptors, Antigen, T-Cell/immunology
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