Survivin-specific T cell receptor targets tumor but not T cells
Caroline Arber, … , Gianpietro Dotti, Barbara Savoldo
Caroline Arber, … , Gianpietro Dotti, Barbara Savoldo
Published November 21, 2014
Citation Information: J Clin Invest. 2015;125(1):157-168. https://doi.org/10.1172/JCI75876.
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Research Article Immunology

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

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

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Figure 1

Survivin-specific T cell clone with antitumor effects in the absence of toxicity.

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Survivin-specific T cell clone with antitumor effects in the absence of ...
(A) FACS analysis of the survivin-specific T cell clone stained for CD8 and the LML-specific or irrelevant tetramer. (B) T cell avidity assessed by IFN-γ ELISpot assays of the irrelevant clone against the LML peptide (black bars) and the survivin-specific clone against the LML (gray bars) or the ELT peptides (white bars). SFCs per 105 cells. Data represent the mean ± SD of triplicate experiments. (C) T cell avidity assessed by 51Cr-release assay against LML- (squares, solid line) or ELT-pulsed T2 cells (triangles, dashed line). Data show the mean ± SD of triplicates of the specific lysis at a 10:1 E/T ratio. (D) Antitumor activity by 51Cr-release assay of an irrelevant (left panel) and a survivin-specific (right panel) clone derived from the same donor against the HLA-A*02+survivin+ target cell lines BV173 and U266 and the HLA-A*02–survivin+ target cell line HL-60. Data represent the mean ± SD of 3 technical replicates of 1 experiment. Two independent experiments were performed in triplicate. (E) Antileukemic activity and absence of toxicity to normal hematopoietic progenitor cells by CFU assay of the survivin-specific clone (white squares) and the irrelevant clone (black circles) against HLA-A*02+survivin+ primary leukemic blasts from 2 CML blast crisis patients and 1 HLA-A*02+ normal BM donor. Data represent the mean ± SD of 3 independent experiments performed in duplicate. *P < 0.001; **P = 0.001 by Student’s t test. (F) Absence of T cell fratricide, assessed as fold expansion over a 3-week culture period after superexpansion of the survivin-specific (white squares, dashed line) and irrelevant (black circles, solid line) clones.