Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

Raman, Marine C. C., Rizkallah, Pierre, Simmons, Ruth, Donnellan, Zoe, Dukes, Joseph, Bossi, Giovanna, Le Provost, Gabrielle S., Todorov, Penio, Baston, Emma, Hickman, Emma, Mahon, Tara, Hassan, Namir, Vuidepot, Annelise, Sami, Malkit, Cole, David and Jakobsen, Bent K. 2016. Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy. Scientific Reports 6 , 18851. 10.1038/srep18851

[img]
Preview
PDF - Published Version
Download (2MB) | Preview

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Nature Publishing Group
ISSN: 2045-2322
Funders: Wellcome
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 27 November 2015
Last Modified: 17 Jun 2019 10:04
URI: http://orca.cf.ac.uk/id/eprint/86283

Citation Data

Cited 29 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics