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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigen Presentation
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Antigens, Neoplasm / chemistry
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology*
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Antigens, Neoplasm / metabolism*
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Cardiotoxicity
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Cell Line
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Connectin / chemistry
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Connectin / immunology
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Connectin / metabolism
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Cross Reactions / immunology*
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Epitopes, T-Lymphocyte / chemistry
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Epitopes, T-Lymphocyte / immunology
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Genetic Engineering
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Humans
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Immunotherapy / adverse effects*
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Immunotherapy / methods*
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Models, Molecular
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Molecular Mimicry*
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Mutation
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Neoplasm Proteins / genetics
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Neoplasm Proteins / immunology
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Neoplasm Proteins / metabolism
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Peptide Fragments / chemistry
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Peptide Fragments / immunology
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Protein Binding / immunology
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Protein Conformation
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / metabolism*
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Antigen, T-Cell, alpha-beta / metabolism
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T-Cell Antigen Receptor Specificity / immunology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
Substances
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Antigens, Neoplasm
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Connectin
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Epitopes, T-Lymphocyte
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MAGEA3 protein, human
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Neoplasm Proteins
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Peptide Fragments
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Receptors, Antigen, T-Cell
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Receptors, Antigen, T-Cell, alpha-beta