Cancer immunotherapies, particularly checkpoint inhibitors, have emerged as highly promising approaches for treatment of a variety of solid tumors, including recurrent ovarian cancer. While dramatic clinical benefit is observed in a subset of patients with ovarian cancer, the majority of ovarian cancer patients do not respond to checkpoint inhibitors, thus combinatorial treatments are sorely needed. Immune competent pre-clinical animal models are crucial to test emerging treatment strategies and for the identification of biomarkers to predict response to therapy.
As results from immune competent preclinical models are often translated into clinical trials, we sought to investigate whether slight variability related to animal housing and/or breeding practices in the same strain could impact experimental outcomes related to immunotherapy. We conducted animal studies using C57BL/6J mice purchased from Jackson Laboratories (Cat# 000664) 2 weeks prior to experimental use (Jax) and using the same mouse strain purchased from Jackson Laboratories but bred within our institution for a period of 6 months prior to use (Jax-R). Using the gold standard ID8 murine metastatic intraperitoneal ovarian cancer model we tested the therapeutic efficacy of anti-PD-1 monotherapy in both Jax and Jax-R animals. Aged-matched female mice were housed under the same conditions for 2 weeks prior to tumor inoculation and for the duration of study. Strikingly, we noted that while anti-PD-1 monotherapy had absolutely no effect on tumor growth or survival of Jax mice, the Jax-R animals showed dramatic tumor growth control and significantly improved long term survival. Tumor progression and survival was similar across sub-strains in untreated control animals, suggesting that the observed differences in treatment outcome following anti-PD-1 treatment were not simply due to intrinsic differences between the animals. Response to treatment was also associated with increased frequencies of circulating CD4+ and CD8+ T cells in the Jax-R mice compared with the Jax animals.
Although major variations in age, animal strain and gut microbiome can dramatically impact upon the efficacy of checkpoint inhibitors, our findings demonstrate that even minute changes within sub-strains recently derived from the same founder animals could result in significantly different survival and pre-clinical outcome. Thus, immunotherapy results obtained from immune competent animal studies need to be interpreted with caution when designing future immunotherapy trials.
Citation Format: AJ Robert Mcgray, Kristen Starbuck, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. Minute variation in murine ovarian cancer preclinical models significantly impact immunotherapy results obtained for clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1623. doi:10.1158/1538-7445.AM2017-1623