In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. LB-106-LB-106
Abstract:
Introduction: Innovative therapies are urgently warranted to cure patients with advanced Ewing sarcoma (ES). Specific cellular-based approaches for immunotherapy of solid cancers show promising results in first clinical trials. Mostly, CD8+ effector T cells are genetically modified to recognize and kill tumor cells. In organ transplantation, alloreactive CD4+ T helper 1 cells have shown to be an underestimated key player in allo-rejection. In previous works we observed massive CD4+ cell tissue-infiltration in tumor-free Rag2-/-c-/- mice after adoptive transfer of ES-specific CD8+ T cells combined with peripheral mononuclear cells in tumor bearing mice, suggesting an important role of CD4+ cells in disease control. In this study we transduce CD4+ T cells from healthy donors with an HLA class I allorepertoire-derived TCR specific for the ES-associated antigen STEAP1130 for which in vivo ES control by adoptively transferring CD8+ cells with the same transgene was demonstrated in previous works. Methods: STEAP1/HLA-A*02:01 specific TCR transgenic CD4+ T cells were generated and characterized by flow cytometry, interferon-, granzyme-B release and xCelligence assays to study direct cytotoxicity and tumor growth inhibition, in comparison to STEAP1/HLA-A*02:01 specific TCR transgenic CD8+ T cells. In vivo functionality was validated in Rag2-/-c-/- mice. Results: STEAP1/HLA-A*02:01 specific TCR CD4+ transduced T cells exhibit high peptide specificity. In vitro, CD4+ TCR transgenic T cells show similar tumor growth inhibition compared to CD8+ cells with the same transgene. Furthermore, in vivo data suggest a synergistic anti-ES effect of CD4+ and CD8+ cells transduced with the same STEAP1/HLA-A*02:01 specific TCR. Conclusion: STEAP1/HLA-A*02:01 TCR transgenic CD4+ T cells exhibit direct cytotoxicity and execute synergistic helper functions. Combination of adoptively transferred TCR transgenic CD4+ and CD8+ T cells may result in better tumor control compared to transfer of respective TCR transgenic CD4+ or CD8+ T cells alone. * U.T. and S.E.G.B. share senior authorship Citation Format: Sebastian J. Schober, Melanie Thiede, David Schirmer, Dirk Wohlleber, Guenther Richter, Dirk H. Busch, Uwe Thiel, Stefan E. Burdach. Allorepertoire-derived HLA class I/peptide-specific T cell receptor transgenic CD4+ T cells mediate antitumor responses in Ewing sarcoma mimicking allo-rejection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-106.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-LB-106
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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