Survivin-specific T cell receptor targets tumor but not T cells
Caroline Arber, Xiang Feng, Harshal Abhyankar, Errika Romero, Meng-Fen Wu, Helen E. Heslop, Patrick Barth, Gianpietro Dotti, Barbara Savoldo
Caroline Arber, Xiang Feng, Harshal Abhyankar, Errika Romero, Meng-Fen Wu, Helen E. Heslop, Patrick Barth, Gianpietro Dotti, Barbara Savoldo
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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 4

Survivin-specific TCR–redirected T cells have antitumor activity in vitro, while lacking toxicity against normal hematopoietic stem/progenitor cells.

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Survivin-specific TCR–redirected T cells have antitumor activity in vitr...
(A) 51Cr-release assays of survivin-specific TCR+ TD (white squares) and NT control T cells (black circles) against HLA-A*02+survivin+ cancer cell lines BV173 and U266 and the HLA-A*02–survivin+ targets HL-60 and K562. Symbols indicate the mean of triplicates per donor; error bars represent the mean ± SD of the percentage of specific lysis at an E/T ratio of 20:1 (n = 12 donors). *P < 0.001; **P = 0.003 by Student’s t test. (B) HLA restriction of TCR+ TD (white symbols) and NT T cells (black symbols) assessed by preincubation of BV173 (left panel, triangles) or U266 (right panel, circles) with HLA class I–blocking Ab (dotted lines), HLA class II–blocking Ab (dashed lines), or in the absence of Ab (solid lines). Data represent the mean ± SD of 3 technical replicates from 1 donor. Cells from 2 donors were analyzed. (C) Quantification of residual tumor cells in cocultures on day 5 of TCR+ TD (open squares) and NT (black circles) T cells cultured with BV173, U266, K562, and HL-60 cells (E/T 5:1). Mean ± SD of residual tumor cells (n = 6). *P < 0.001 and ** P = 0.02 by Student’s t test. (D) IFN-γ production by TCR+ TD (white squares) and NT (black circles) T cells against BV173, U266, K562, and HL-60 cells by ELISpot assay. Symbols represent the mean of triplicates per donor; error bars indicate the mean ± SD (n = 5). *P < 0.001 and **P = 0.01 by Student’s t test. (E–G) Assessment of leukemic colony formation by TCR+ TD (white squares) and NT (black circles) T cells against HLA-A*02+ CML blast crisis (n = 2) and AML (n = 3) (E), HLA-A*02– leukemic blasts (F), and HLA-A*02+ healthy donor–derived BM (n = 1) or CB (n = 4) progenitor cells (G). Data represent the mean ± SD of CFU plated in duplicate for 5 donors. *P < 0.001 by Student’s t test.