title: Pappalysin-1 T cell receptor transgenic allo-restricted T cells kill Ewing sarcomain vitroandin vivo.
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 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-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 TCR identification, retrovirally TCR transduced CD8+T cells were assessed for theirin vitrospecificity andin vivoefficacy 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 toward HLA-A*02:01+/PAPPA+ES cell lines. We furthermore detected circulating TCR transgenic T cells in the blood in Rag2-/-γc-/-mice andin vivoengraftment 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.
authors.affiliation: Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics and Children's Cancer Research Center, Klinikum rechts der Isar, Technische Universität München , München, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kirschner
authors.affiliation: Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics and Children's Cancer Research Center, Klinikum rechts der Isar, Technische Universität München , München, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Thiede
authors.affiliation: Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology of the LMU Munich, München, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Thomas G P
authors.identifier: 0000-0003-0920-7377
authors.initials: TG
authors.lastname: Grünewald
authors.affiliation: Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology of the LMU Munich , München, Germany.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Alba Rubio
authors.affiliation: Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics and Children's Cancer Research Center, Klinikum rechts der Isar, Technische Universität München, München, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Günther H S
authors.initials: GH
authors.lastname: Richter
authors.affiliation: Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology of the LMU Munich, München, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Comprehensive Cancer Center (CCC) Munich, München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München , München, Germany.
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.affiliation: Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics and Children's Cancer Research Center, Klinikum rechts der Isar, Technische Universität München, München, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Comprehensive Cancer Center (CCC) Munich, München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Burdach
authors.affiliation: Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics and Children's Cancer Research Center, Klinikum rechts der Isar, Technische Universität München , München, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Thiel
keywords: Allogeneic; Ewing sarcoma; PAPPA; Pappalysin; T cell therapy; transgenic TCR