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

Gerald P. Linette, Edward A. Stadtmauer, Marcela V. Maus, Aaron P. Rapoport, Bruce L. Levine, Lyndsey Emery, Leslie Litzky, Adam Bagg, Beatriz M. Carreno, Patrick J. Cimino, Gwendolyn K. Binder-Scholl, Dominic P. Smethurst, Andrew B. Gerry, Nick J. Pumphrey, Alan D. Bennett, Joanna E. Brewer, Joseph Dukes, Jane Harper, Helen K. Tayton-Martin, Bent K. Jakobsen, Namir J. Hassan, Michael Kalos and Carl H. June

Key points

  • 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 (NCT01350401 and NCT01352286).

  • Submitted March 15, 2013.
  • Accepted June 6, 2013.