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

Marine C C Raman1, Pierre J Rizkallah2, Ruth Simmons1

  • 1Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.

Scientific Reports
|January 14, 2016
PubMed

Insights

Enhanced affinity T-cell receptors (TCRs) show promise for cancer immunotherapy but can cause fatal toxicity due to cross-reactivity. This study reveals the structural basis of such cross-reactivity and demonstrates rational design of TCRs with improved antigen specificity.

Area of Science:

  • Immunology
  • Structural Biology
  • Cancer Immunotherapy

Background:

  • Natural T-cell responses are often insufficient for cancer eradication.
  • Enhanced affinity T-cell receptors (TCRs) offer a promising strategy for cancer immunotherapy.
  • Off-target reactivity of engineered TCRs poses a significant safety concern, as evidenced by fatal cardiac toxicity.

Purpose of the Study:

  • To investigate the structural mechanism behind TCR cross-recognition of MAGE-A3 and Titin.
  • To rationally design TCR mutants with improved antigen discrimination for cancer immunotherapy.
  • To provide a proof-of-concept for altering TCR fine specificity towards intended target antigens.

Main Methods:

  • Structural analysis of TCR-epitope interactions.
  • Rational design and engineering of T-cell receptors (TCRs).
  • In vitro and potentially in vivo validation of engineered TCR function and specificity.

Main Results:

  • Elucidation of the structural basis for molecular mimicry between MAGE-A3 and Titin epitopes.
  • Successful design of TCR mutants with enhanced antigen discrimination.
  • Demonstration of a strategy to improve TCR specificity for cancer immunotherapy.

Conclusions:

  • The study provides the first example of direct molecular mimicry causing fatal toxicity via engineered TCRs.
  • High-expression self-antigens on healthy tissues require extreme caution in immunotherapeutic design.
  • Rational engineering of TCRs can improve specificity and mitigate off-target toxicity in cancer immunotherapy.

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