Survivin-specific T cell receptor targets tumor but not T cells

Caroline Arber, Xiang Feng, Harshal Abhyankar, Errika Romero, Meng Fen Wu, Helen Heslop, Patrick Barth, Gianpietro Dotti, Barbara Savoldo

Research output: Contribution to journalArticle

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)157-168
Number of pages12
JournalJournal of Clinical Investigation
Volume125
Issue number1
DOIs
StatePublished - Jan 2 2015

ASJC Scopus subject areas

  • Medicine(all)

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