title: Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy.
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.
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Marine C C
authors.initials: MC
authors.lastname: Raman
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Henry Wellcome building, Heath Park, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Rizkallah
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Simmons
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Donnellan
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Joseph
authors.initials: J
authors.lastname: Dukes
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bossi
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Gabrielle S
authors.initials: GS
authors.lastname: Le Provost
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Penio
authors.initials: P
authors.lastname: Todorov
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Baston
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Hickman
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Tara
authors.initials: T
authors.lastname: Mahon
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Namir
authors.initials: N
authors.lastname: Hassan
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Annelise
authors.initials: A
authors.lastname: Vuidepot
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Malkit
authors.initials: M
authors.lastname: Sami
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Henry Wellcome building, Heath Park, Cardiff, CF14 4XN, United Kingdom.
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.affiliation: Immunocore Limited, 101 Park Drive, Milton Park, Abingdon, Oxon, OX14 4RX, United Kingdom.
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
mesh_terms: D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D066126:Cardiotoxicity; D002460:Cell Line; D064211:Connectin / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D003429:Cross Reactions / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects* / Q000379:methods*; D008958:Models, Molecular; D018716:Molecular Mimicry; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D064211:Connectin; D018984:Epitopes, T-Lymphocyte; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta