Pappalysin-1 T cell receptor transgenic allo-restricted T cells kill Ewing sarcoma and .

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 setting free IGFs. 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 is associated with various cancers. It is overexpressed and required for proliferation in ES. PAPPA also stimulates normal bone growth. We isolated HLA-A02:01/peptide-restricted T cells from A02:01 healthy donors directed against PAPPA, generated by priming with A02:01 PAPPA peptide loaded dendritic cells. After TCR identification, retrovirally TCR transduced CD8 T cells were assessed for their specificity and efficacy in human ES bearing Rag2γc 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 toward HLA-A02:01/PAPPA ES cell lines. We furthermore detected circulating TCR transgenic T cells in the blood in Rag2γc mice and engraftment in bone marrow. Tumor growth in mice with xenografted ES was significantly reduced after treatment with PAPPA-2G6 TCR transgenic T cells in contrast to controls. Tumors of treated mice revealed tumor-infiltrating PAPPA-2G6 TCR transgenic T cells. In summary, we demonstrate that PAPPA is a first-rate target for TCR-based immunotherapy of ES.