Abstract IA13: The Patient-Derived Xenograft Program at The Jackson Laboratory

Abstract

The Patient Derived Xenograft (PDX) Program at The Jackson Laboratory have as its focus, the development of quality surrogates of primary human tumors for the research community, the construction and optimization of murine hosts for human tumor xenografts, and the conduct of research into cancer biology using these PDX models. Begun in 2010, the PDX Program is based on the foundational murine host, the NOD-scid IL2rgnull or NSG (NOD.Cg-Prkdcscid IL2rgtm1wjl/SzJIL2rgtm1wjl) mouse, which lacks T, B, and NK cells and harbors deficiencies in innate immune response due to defects in multiple cytokine receptors including the IL2. 4, 7, 9, 15, and 21 receptors1,2. NSG mice have superior engraftment profiles as compared to other immunodeficient strains. These tumor xenografts in NSG hosts maintain the features of primary of engrafted human tumors including, tumor heterogeneity, three-dimensional architecture, and tumor biology including response to therapeutics. The engraftment rates vary according to tumor types with prostate cancers being among the lowest (3%), and colorectal cancers (66%), melanomas, and glioblastomas being among the best, according to whether the tumors are from metastatic sites, show a higher tumor grade, or have larger amounts of starting tumor material. We currently have 446 PDX models in stock with ~100 in the pipeline, and when coupled with 218 models from our Korean cooperative institution (Ewha University), our total collection is ~664 covering 15 tumor types with none beyond passage number 4 (P4). Most have genomic data available and the Korean PDXs have matching normal tissue and DNA sequence data. Importantly, the human immune system can be engrafted in NSG mice and in the presence of a human tumor, can be used to study tumor-immune cell interactions including response to immune therapeutics. In addition, our colleagues and we have developed genetic modifications of the NSG to provide unique engraftment options: MHC class I and II knockouts to reduce xenogeneic graft-vs.-host disease, expressing HLA-A2 and other HLA class I and II transgenes to develop HLA-restricted human cytotoxic T cells, and IL-6 and prolactin to support engraftment of tumors needing these factors. NSG mice expressing human IL3/GM-CSF/SCF supports the immune reconstitution of myeloid progenitors providing a more complete immune system and has been useful in testing cancer immune therapeutics. With 26 staff dedicated to PDX and NSG experimentation, we provide strains of NSG mice with or without human immune cell reconstitution, and conduct large-scale pharmacological studies in cohorts of PDX models. 1Hidalgo M, Amant F, Biankin AV, Budinská E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Mælandsmo GM, Roman-Roman S, Seoane J, Trusolino L, Villanueva A. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 2014 Sep;4(9):998-1013. 2Shultz LD, Goodwin N, Ishikawa F, Hosur V, Lyons BL, Greiner DL. Human cancer growth and therapy in immunodeficient mouse models. Cold Spring Harbor Protoc. 2014 Jul 1;2014(7):694-708. Citation Format: Edison T. Liu, James Keck, Susie Airhart, Lenny Shultz, Charles Lee, Carol Bult. The Patient-Derived Xenograft Program at The Jackson Laboratory. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA13.