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

Raman, Marine C. C., Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369, 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 ORCID: https://orcid.org/0000-0003-0028-9396 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

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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:	04 May 2023 05:06
URI:	https://orca.cardiff.ac.uk/id/eprint/86283

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