Journal
JOURNAL OF IMMUNOLOGY
Volume 193, Issue 5, Pages 2587-2599Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1302344
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Funding
- National Institutes of Health [1U01CA137070, OD004631]
- American Cancer Society Research Scholar [RSG-09-070-01-LIB]
- Cancer Research Institute Investigator grant
- Pew Scholar in Biomedical Sciences - Pew Trust
- National Institute of General Medical Sciences [5R01GM085586-04]
- American Heart Association predoctoral fellowship
- National Institutes of Health molecular biophysics training grant
- Molecular Oncology and Tumor Immunology National Institutes of Health/National Cancer Institute [5T32CA009161-39]
- New York University Caregiver Intervention Center support grant
- National Institutes of Health/National Cancer Institute [5 P30CA16087-31]
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Adoptive immunotherapy with Ag-specific T lymphocytes is a powerful strategy for cancer treatment. However, most tumor Ags are nonreactive self proteins, which presents an immunotherapy design challenge. Recent studies have shown that tumor-specific TCRs can be transduced into normal PBLs, which persist after transfer in similar to 30% of patients and effectively destroy tumor cells in vivo. Although encouraging, the limited clinical responses underscore the need for enrichment of T cells with desirable antitumor capabilities prior to patient transfer. In this study, we used structure-based design to predict point mutations of a TCR (DMF5) that enhance its binding affinity for an agonist tumor Ag-MHC (peptide-MHC [pMHC]), Mart-1 (27L)-HLA-A2, which elicits full T cell activation to trigger immune responses. We analyzed the effects of selected TCR point mutations on T cell activation potency and analyzed cross-reactivity with related Ags. Our results showed that the mutated TCRs had improved T cell activation potency while retaining a high degree of specificity. Such affinity-optimized TCRs have demonstrated to be very specific for Mart-1 (27L), the epitope for which they were structurally designed. Although of somewhat limited clinical relevance, these studies open the possibility for future structural-based studies that could potentially be used in adoptive immunotherapy to treat melanoma while avoiding adverse autoimmunity-derived effects.
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