Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy
| Autor: | Marine C C Raman, Pierre J Rizkallah, Ruth Simmons, Zoe Donnellan, Joseph Dukes, Giovanna Bossi, Gabrielle S Le Provost, Penio Todorov, Emma Baston, Emma Hickman, Tara Mahon, Namir Hassan, Annelise Vuidepot, Malkit Sami, David K Cole, Bent K. Jakobsen |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Antigen Presentation Protein Conformation Receptors Antigen T-Cell alpha-beta Molecular Mimicry Receptors Antigen T-Cell Antigen-Presenting Cells Epitopes T-Lymphocyte T-Cell Antigen Receptor Specificity Cross Reactions R1 Cardiotoxicity Peptide Fragments Article Cell Line Neoplasm Proteins Antigens Neoplasm T-Lymphocyte Subsets Mutation Humans Connectin Immunotherapy Genetic Engineering Protein Binding |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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