title: Survivin-specific T cell receptor targets tumor but not T cells.
abstract: Survivin is a tumor-associated antigen (TAA) that inhibits apoptosis and is widely overexpressed in cancer cells; therefore, survivin has potential as a target for cancer immunotherapy. Application of HLA-A2-restricted survivin-specific T cell receptors (TCRs) isolated from allogeneic HLA-mismatched TCR repertoires has, however, been impeded by the inability of these TCRs to distinguish healthy cells expressing low levels of survivin from cancer cells with high survivin expression levels. Here, we identified an HLA-A2-restricted survivin-specific TCR isolated from autologous TCR repertoires that targets tumor cells in vitro and in vivo but does not cause fratricidal toxicity. Molecular modeling of the TCR-peptide-HLA ternary complexes and alanine scanning revealed that the autologously derived TCRs had tighter interactions with the survivin peptide than did fratricidal TCRs. Similar recognition patterns were observed among 7 additional TAA-specific TCRs isolated from allogeneic versus autologous repertoires. Together, the results from this study indicate that maximal peptide recognition is key for TCR selectivity and likely critical for reducing unwanted off-target toxicities. Moreover, isolating TCRs from autologous repertoires to maximize TCR selectivity has potential as a useful strategy to identify and select other shared tumor- and self-antigen-specific TCRs and ensure selective antitumor activity.
authors.forename: Caroline
authors.initials: C
authors.lastname: Arber
authors.forename: Xiang
authors.initials: X
authors.lastname: Feng
authors.forename: Harshal
authors.initials: H
authors.lastname: Abhyankar
authors.forename: Errika
authors.initials: E
authors.lastname: Romero
authors.forename: Meng-Fen
authors.initials: MF
authors.lastname: Wu
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Patrick
authors.initials: P
authors.lastname: Barth
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D003429:Cross Reactions; D018922:HL-60 Cells; D006801:Humans; D007167:Immunotherapy; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology*; D020014:K562 Cells; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D051379:Mice; D009368:Neoplasm Transplantation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D000077022:Survivin; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D011948:Receptors, Antigen, T-Cell; D000077022:Survivin