title: Specific increase in potency via structure-based design of a TCR.
abstract: 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 ∼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.
authors: Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; Program in Structural Biology, New York University School of Medicine, New York, NY 10016;
authors: Karolina
authors: K
authors: Malecek
authors: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;
authors: Arsen
authors: A
authors: Grigoryan
authors: Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016;
authors: Shi
authors: S
authors: Zhong
authors: Department of Chemistry, New York University, New York, NY 10012;
authors: Wei Jun
authors: WJ
authors: Gu
authors: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors: Laura A
authors: LA
authors: Johnson
authors: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors: Steven A
authors: SA
authors: Rosenberg
authors: Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;
authors: Timothy
authors: T
authors: Cardozo
authors: Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016; Program in Structural Biology, New York University School of Medicine, New York, NY 10016; Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY 10016 Michelle.Krogsgaard@nyumc.org.
authors: Michelle
authors: M
authors: Krogsgaard
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D058965:MART-1 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D017354:Point Mutation; D015202:Protein Engineering; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D013329:Structure-Activity Relationship
chemical_list: D018984:Epitopes, T-Lymphocyte; D058965:MART-1 Antigen; D010455:Peptides; D011948:Receptors, Antigen, T-Cell