Abstract 692: Pappalysin-1 is a suitable target for T cell receptor transgenic T cells to kill Ewing sarcoma in vivo and in vitro

Abstract

Pregnancy-associated plasma protein-A (PAPPA), also known as pappalysin, is a member of the insulin like growth factor (IGF) family. PAPPA acts as a protease, cleaving IGF inhibitors, i.e. IGF binding proteins (IGFBPs), thereby releasing IGFs from IGFBPs. The insulin/IGF-axis is involved in cancer in general and in Ewing sarcoma (ES) in particular. ES is a highly malignant bone tumor characterized by early metastatic spread. PAPPA stimulates normal bone growth, and is also associated with various cancers. In particular, PAPPA is overexpressed and required for proliferation in ES. We isolated HLA-A*02:01⁺/peptide restricted T cells from A*02:01^- healthy donors directed against PAPPA, generated by priming with A*02:01⁺ PAPPA peptide-loaded dendritic cells. After T cell receptor (TCR) identification, retrovirally TCR transduced CD8⁺ T cells were assessed for their in vitro specificity and in vivo efficacy in human ES bearing Rag2^-/-γc^-/- mice. Engraftment in mice and tumor infiltration of TCR transgenic T cells in the mice was evaluated. The TCR transgenic T cell clone PAPPA-2G6 demonstrated specific reactivity towards HLA-A*02:01⁺/PAPPA⁺ ES cell lines. We furthermore detected circulating TCR transgenic T cells in the blood in Rag2^-/-γc^-/- mice and in vivo engraftment of the in bone marrow. Tumor growth in mice with xenografted ES was significantly reduced after treatment with PAPPA-2G6 TCR transgenic T cells compared to controls, and tumors from treated mice revealed tumor infiltrating PAPPA-2G6 TCR transgenic T cells. In summary, we demonstrate that PAPPA is a promising target for TCR based immunotherapy of ES. We demonstrate that TCR transgenic T cells recognize this target, home to the tumor, and causes tumor regression in a preclinical mouse model.

Citation Format: Uwe Thiel, Andreas Kirschner, Melanie Thiede, Thomas GP Grünewald, Rebeca Alba Rubio, Günther Richter, Thomas Kirchner, Dirk Busch, Poul Sorensen, Stefan Burdach. Pappalysin-1 is a suitable target for T cell receptor transgenic T cells to kill Ewing sarcoma in vivo and in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 692. doi:10.1158/1538-7445.AM2017-692