Abstract 2281: Building mouse tumor derived allogragfts for immune-oncology research

Abstract

Abstract Immuno-oncology is an area under intensive investigation, however, many questions remain to be answered due to lack of sufficient number of adequate experimental models: 1) why only subsets of patients respond? 2) who will respond (signature)? 3) what can we do to make more patients to respond? Patient derived xenograft (PDX or HuPrime®) mirrors patients’ histopathological/genetic profiles, considered more predictive than traditional human cell line derived xenograft (CDX) and also syngenic mouse cell derived models, due to the primary natures of PDX. On the other hand, both xenografts (PDX/CDX) grow in absence of immunity, thus unsuitable for immune-oncology research. Limited types/numbers of available syngenic cells also restrict its application. Genetically engineered mutant mouse cancer model (GEMM) are diverse (types/numbers)1-5, grow in immune-environment, and are primary tumors. However, GEMM has logistic limitation for pharmacology research for high cost and high variations in tumor development (spontaneous) in type/time. We set out to create a library of primary mouse tumor allografts (MuPrimeTM) as standard experimental models, aiming at overcoming these limitations. We established a number of such allografts and are profiling them for growth, histopathology, genomic (RNAseq), and standard of care (SOC). We are also charactering their immune-oncology properties: tumor-infiltrating immune cells, including different subtypes of T-cells (CTL, Treg), as well as their functional activation/suppression and tumor responses to immune-modulating agents. MBR6004 is an allograft derived from a breast adenocarcinoma of GEMM-MMTV-PyVT in FVB/N mice1, which expressed medium level Her2 but negative for ER and PR, and is resistant to Docetaxel(SOC). It expresses low-level PD-L1(CD274)/L2 and seems insensitive to PD-1 antibody treatment. MCR6013, an allograft of a colon adenocarcinoma derived from GEMM-C57BL/6J-ApcMin/JNju3-5, are currently being profiled. MPR6003, an allograft of transgenic adenocarcinoma mouse prostate (TRAMP) in C57BL/6 mice6-8, grow both orthotopically and subcutaneously, and are also being profiled. M6011, an allograft derived from a spontaneous tumor in Balb/c mouse with high Her2 expression, has apparent infiltration of T-cells, including Treg, but negative for PD-L1. We are currently characterizing its histopathology and other property. MLY1014, an allograft of a spontaneous lymphoma derived from Balb/c, is also being profiled. In general, these allografts keep the original primary tumor histopathology, but distinct from conventional syngenic cell line derived tumors, a contrast seen between PDX vs. CDX. The models grow robustly after engraftment, thus ideal for pharmacology evaluation. Our ongoing studies will provide a useful platform with normal immunity for drug evaluation, particularly for immune-oncology agents. Citation Format: Xiaoyu An, Jinping Liu, Jie Cai, Jean-Pierre Wery, Henry Qixiang Li. Building mouse tumor derived allogragfts for immune-oncology research. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2281. doi:10.1158/1538-7445.AM2015-2281