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

作者：Raman Marine C C; Rizkallah Pierre J; 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 K^*; Jakobsen Bent K

来源：Scientific Reports, 2016, 6(1): 18851.

DOI：10.1038/srep18851

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.

• 出版日期2016-1-13