Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy

Sci Rep. 2016 Jan 13;6:18851. doi: 10.1038/srep18851.

Abstract

Natural T-cell responses generally lack the potency to eradicate cancer. Enhanced affinity T-cell receptors (TCRs) provide an ideal approach to target cancer cells, with emerging clinical data showing significant promise. Nevertheless, the risk of off target reactivity remains a key concern, as exemplified in a recent clinical report describing fatal cardiac toxicity, following administration of MAGE-A3 specific TCR-engineered T-cells, mediated through cross-reactivity with an unrelated epitope from the Titin protein presented on cardiac tissue. Here, we investigated the structural mechanism enabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally design mutants with improved antigen discrimination, providing a proof-of-concept strategy for altering the fine specificity of a TCR towards an intended target antigen. This study represents the first example of direct molecular mimicry leading to clinically relevant fatal toxicity, mediated by a modified enhanced affinity TCR designed for cancer immunotherapy. Furthermore, these data demonstrate that self-antigens that are expressed at high levels on healthy tissue should be treated with extreme caution when designing immuno-therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Antigens, Neoplasm / chemistry
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • Antigens, Neoplasm / metabolism*
  • Cardiotoxicity
  • Cell Line
  • Connectin / chemistry
  • Connectin / immunology
  • Connectin / metabolism
  • Cross Reactions / immunology*
  • Epitopes, T-Lymphocyte / chemistry
  • Epitopes, T-Lymphocyte / immunology
  • Genetic Engineering
  • Humans
  • Immunotherapy / adverse effects*
  • Immunotherapy / methods*
  • Models, Molecular
  • Molecular Mimicry*
  • Mutation
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology
  • Neoplasm Proteins / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • Protein Binding / immunology
  • Protein Conformation
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • T-Cell Antigen Receptor Specificity / immunology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism

Substances

  • Antigens, Neoplasm
  • Connectin
  • Epitopes, T-Lymphocyte
  • MAGEA3 protein, human
  • Neoplasm Proteins
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Receptors, Antigen, T-Cell, alpha-beta