Structure-guided design of the TIL1383I T cell receptor

• DOI: 10.4049/jimmunol.204.supp.80.3
• Publication Date: 2023-01-01T14:16:22Z
• Authors: Jesus A Alonso; Nishant K Singh; Lauren Devancaze; Jason Devlin; Brian M Baker
• Keywords: Cancer Immunotherapy

Abstract T cell therapy is an exciting form of cancer immunotherapy in which cells are engineered to target specific tumor antigens. We employed a structure-guided design approach with the goal engineering safer and more effective variant TIL1383I receptor (TCR) currently under study clinical trials for malignant melanoma. Using our unpublished structure we process designing panel TCR variants identifying candidates that improve “focus” towards tyrosinase antigen presented on MHC class I molecule HLA-A2. Structural analysis revealed key residues, particularly beta-chain residues E97, G101, L102, responsible engaging peptide bound The crystal complex tyrosinase-HLA-A2 also highlighted its uncharacteristic binding geometry therefore hypothesize this orientation associated observed CD8 co-receptor independence TIL1383I. Indeed, functional TIL1383I-transduced CD8-positive CD8-negative cells, transduced expressing truncated lacking intracellular LCK signaling domain, by HLA-A2 mutants outline independence. Combined interrogation cross-reactivity via positional scanning library approach, resulted identification improved affinities as well understanding structural characteristics may contribute TIL1383I’s