Abstract 4183: Utility of the highly immunodeficient SRG rat for combined drug efficacy, pharmacokinetics, and toxicology studies in tumor-bearing animals

Abstract

Abstract Immunodeficient rodents are vital pre-clinical disease models. Historically, immunodeficient mice have been standard for hosting human cell and tissue xenografts, enabling cancer drug efficacy and tolerability testing. However, an immunodeficient rat that supports a variety of human cancer types provides a larger model for easier surgical manipulation and serial blood and tumor tissue sampling, allowing for efficacy, pharmacokinetics, and toxicology testing in the same animal. We created a Sprague Dawley Rag2 -/-, Il2rg -/- rat (SRG Rat®; SRG) that is highly supportive of human cell and tissue engraftment. The SRG rat lacks B, T, and NK cells and is more immunodeficient than the Nude rat. Here we show comparative pathology between the SRG rat and its parental strain, the CRL Sprague Dawley (CD). We also present data from an efficacy study in tumor bearing SRG rats, demonstrating that serial blood draws and tumor biopsies can be performed in tumor bearing animals to assess drug pharmacokinetics and pharmacodynamics within a single study. First, we assessed 10 SRG (5/sex) and 10 CD (5/sex) at 8-10 weeks of age. Body weight, hematology, and clinical chemistry parameters were measured. Microscopic examinations were performed on routine H&E slide preparations. Male and female SRG displayed lower mean body weight when compared to sex- and age-matched CD. Compared to CD, SRG had reduced lymphoid tissue and circulating monocytes, and highly reduced circulating lymphocytes, neutrophils, eosinophils, and basophils; expected phenotypes for this severely immunodeficient rat. Thymus was not present in SRG rats, spleens were grossly smaller, and bone marrow cellularity was decreased compared to CD. Microscopically, mandibular lymph nodes and lymphoid tissue in spleen, lung, and intestine were not observed in SRG rats, consistent with the 92% decrease in circulating lymphocytes. To demonstrate the utility of the SRG for tumor inhibition, pharmacokinetics, and pharmacodynamics, we inoculated rats with human VCaP prostate cancer cell-derived tumors, then treated these animals and collected serial blood samples and tumor biopsies to assess tumor biomarkers. Treatment led to decreased PSA and AR, two key proteins expressed in prostate cancer, correlating to decreased tumor growth. These data demonstrate that the SRG rat is suitable for toxicology studies and has comparable pathology to the CD rat, except for reduced lymphoid tissue and WBCs, which are expected phenotypes. In addition, the SRG rat supports the growth of human cancer tissue for treatment studies. The large size of the SRG rat and comparative pathology to the CD rat support its value as an immunodeficient model for assessing toxicity during efficacy testing for de-risking safety concerns in the presence of the human target tissue. Citation Format: Diane Begemann, Cynthia Dunn, Darrell Robertson, Lauren Keach, Emily Baldwin, R. Grace Walton, Alex Van Engelenburg, Jessica Durrant, Laura Healy, Koh Meng Aw Yong, Michael J. Schlosser, Fallon K. Noto. Utility of the highly immunodeficient SRG rat for combined drug efficacy, pharmacokinetics, and toxicology studies in tumor-bearing animals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4183.