Abstract LB-106: Allorepertoire-derived HLA class I/peptide-specific T cell receptor transgenic CD4+ T cells mediate antitumor responses in Ewing sarcoma mimicking allo-rejection

• Published in: Cancer research (Chicago, Ill.) Vol. 78; no. 13_Supplement; p. LB-106
• Main Authors: Schober, Sebastian J., Thiede, Melanie, Schirmer, David, Wohlleber, Dirk, Richter, Guenther, Busch, Dirk H., Thiel, Uwe, Burdach, Stefan E.
• Format: Journal Article
• Language: English
• Published: 01-07-2018
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-LB-106

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.