Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma

Blood. 2013 Aug 8;122(6):863-71. doi: 10.1182/blood-2013-03-490565. Epub 2013 Jun 14.


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.

MeSH terms

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


  • Antigens, Neoplasm
  • Connectin
  • Cytokines
  • Epitopes
  • HLA-A Antigens
  • MAGEA3 protein, human
  • Muscle Proteins
  • Neoplasm Proteins
  • Peptides
  • Receptors, Antigen, T-Cell
  • TTN protein, human
  • Protein Kinases