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Schirmer, D.* ; Gruenewald, T.G.P.* ; Klar, R.* ; Schmidt, O.* ; Wohlleber, D.* ; Rubio, R.A.* ; Uckert, W.* ; Thiel, U.* ; Bohne, F. ; Busch, D.H.* ; Krackhardt, A.M.* ; Burdach, S.* ; Richter, G.H.S.*

Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity.

OncoImmunology 5:e1175795 (2016)

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Open Access Green as soon as Postprint is submitted to ZB.

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Pediatric cancers, including Ewing sarcoma (ES), are only weakly immunogenic and the tumor-patients' immune system often is devoid of effector T cells for tumor elimination. Based on expression profiling technology, targetable tumor-associated antigens (TAA) are identified and exploited for engineered T-cell therapy. Here, the specific recognition and lytic potential of transgenic allo-restricted CD8(+) T cells, directed against the ES-associated antigen 6-transmembrane epithelial antigen of the prostate 1 (STEAP1), was examined. Following repetitive STEAP1(130) peptide-driven stimulations with HLA-A*02:01(+) dendritic cells (DC), allo-restricted HLA-A*02:01(-)CD8(+) T cells were sorted with HLA-A*02:01/peptide multimers and expanded by limiting dilution. After functional analysis of suitable T cell clones via ELISpot, flow cytometry and xCELLigence assay, T cell receptors' (TCR) alpha- and beta-chains were identified, cloned into retroviral vectors, codon optimized, transfected into HLA-A*02:01(-) primary T cell populations and tested again for specificity and lytic capacity in vitro and in a Rag2(-/-) gamma c(-/-) mouse model. Initially generated transgenic T cells specifically recognized STEAP1(130)-pulsed or transfected cells in the context of HLA-A*02:01 with minimal cross-reactivity as determined by specific interferon-g (IFN gamma) release, lysed cells and inhibited growth of HLA-A*02:01(+) ES lines more effectively than HLA-A*02:01(-) ES lines. In vivo tumor growth was inhibited more effectively with transgenic STEAP1(130)-specific T cells than with unspecific T cells. Our results identify TCRs capable of recognizing and inhibiting growth of STEAP1-expressing HLA-A*02:01(+) ES cells in vitro and in vivo in a highly restricted manner. As STEAP1 is overexpressed in a wide variety of cancers, we anticipate these STEAP1-specific TCRs to be potentially useful for immunotherapy of other STEAP1-expressing tumors.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Allo-restricted T Cells ; Ewing Sarcoma ; Steap1 ; Tcr-transgenic T Cells; Total-body Irradiation; Advanced Ewing Tumors; Versus-host-disease; Sarcoma Family; Molecular Pathogenesis; European Intergroup; Antitumor-activity; Prognostic-factors; Genomic Landscape; Poor-prognosis

ISSN (print) / ISBN 2162-4011

e-ISSN 2162-402X

Journal OncoImmunology

Quellenangaben Volume: 5, Issue: 6, Article Number: e1175795

Publisher Taylor & Francis

Publishing Place Philadelphia

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Virology (VIRO)