Abstract B36: Novel immunodeficient rat models capable of supporting the growth of human tumor xenografts

Abstract

Abstract Mouse models of human cancer have paved the way for studying cancer biology and genomics and their effects on cancer growth kinetics, propensity for metastasis, and treatment response. In addition, human cancer xenografts provide the opportunity to study cancer cell interactions with host stroma and tumor morphology. A plethora of genetically immunodeficient mouse models exist with different immune phenotypes, resulting in significant variability in tumor take rates and growth kinetics for a wide range of human cancer cell lines and patient-derived xenografts (PDX). Inconsistent or poor growth in these immunodeficient models have made downstream analysis and drug efficacy testing difficult. As a result, a significant number of mice are needed for drug efficacy screening to achieve a cohort of animals with tumors of similar size with similar tumor growth kinetics for treatment. It is possible that these cell lines might grow more consistently in a different immunodeficient model, such as an immunodeficient rat. Until recently, the only immunodeficient rat that existed was the nude (NIH-Foxn1rnu; RNU) rat. This rat lacks T cells, but maintains a normal repertoire of all other immune cells, including B and NK cells. As such, there are a limited number of human cancer cell lines that can survive in the nude rat. We have created a genetically modified rat with a functional mutation of the Rag2 gene (Sprague Dawley – Rag2 null; SDR), resulting in a loss of mature B and T cells. In addition, we have created a Rag2/Il2rg double knockout rat (Sprague Dawley – Rag2; Il2rg null; SRG) that lacks mature B cells, T cells, and has fewer NK cells than wild-type Sprague Dawley rats. We have shown that the SDR rat is permissive for solid tumor growth of the human acute lymphocytic leukemia REH cell line, human glioblastoma U87MG cell line, human non-small cell lung cancer H358 cell line, and cell lines derived from ovarian and endometrial PDX samples. In some cases, tumor growth kinetics are superior in the SDR rat compared with immunodeficient mouse models. We have demonstrated that the human prostate cancer cell line, VCaP, which has poor engraftment efficiency and growth kinetics in the mouse, grows well in the SRG rat. The SRG rat is currently being validated for growth kinetics of other human cancer cell lines and PDX tissues. In addition, we are developing several disseminated human leukemia models in the SRG rat and creating immune-humanized mice and rats to be used in conjunction with human tumor xenografts for immunotherapy efficacy studies. Citation Format: Fallon K. Noto, Kamesh Ravi, Angela Arey, Christopher McClain, Wei Zhang, Goutham Narla, Jack Crawford, Tseten Yeshi. Novel immunodeficient rat models capable of supporting the growth of human tumor xenografts [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B36.