Abstract 2749: Age-related cancer drug toxicity and efficacy, and immune modulation in C57BL6J syngeneic model
Authors: Yang Jiwon , Schile Andrew , Cheng Mingshan , Keck James 
Published: September 2020

Cancer has a higher incidence in the elderly and immunotherapy is widely applied to this population. However, the majority of preclinical studies assessing drug toxicity and efficacy have been done in young healthy mice, which could lead to translational failure. The goals of this study were to establish tumor models in aged mice for a better representation of cancer patients, and to examine the effects of aging on tumor growth, toxicity and efficacy of cancer treatment, and immune cell populations in syngeneic models using C57BL/6J mice of different ages. Young (7 weeks), mid-aged (56-58 weeks) and aged (76-78 weeks) C57BL/6J female mice were used for this study. To evaluate the maximum tolerated dose, young and aged mice were dosed with the standard of care cancer drugs (docetaxel, cisplatin, and doxorubicin) and body weight was monitored three times a week until mice reached endpoint criteria. Syngeneic tumor models were established using three different mouse cancer cell lines, B16-F10 melanoma, MC38 colon adenocarcinoma, and E0771 breast cancer. Several different concentrations of cells were injected subcutaneously and tumor growth kinetics were evaluated three times weekly. For efficacy study, mice were randomly assigned to isotype control or Anti-PD1 (8 mg/kg) treatment groups, and were dosed intravenously twice weekly for 3 weeks. One week after the last dose, whole blood and tumor samples were collected for flow cytometry analysis for immune cell profiling on B cells, T cells, NK cells. Aged mice showed higher toxicity against docetaxel, cisplatin, and doxorubicin compared to their young counterparts. Age-related tumor growth kinetics varied based on tumor models. Aging did not affect tumor growth kinetics of B16-F10 tumors, while aged mice showed slowed growth of MC38 tumors and faster growth of E0771 tumors. Across all tumor models, aged mice lost body weight while young mice gained body weight over the course of tumor growth, suggesting potential cancer-related cachexia in aged mice. Comparisons of PD-1 response in the various age groups with different tumors showed that anti-PD1 treatment significantly slowed down tumor growth in mid-aged (58 weeks) mice with B16-F10 tumors, but not in young or aged mice. However, the same treatment showed significant suppression of tumor growth in all age groups with the MC38 tumors. This effect might be partly caused by changes in the immune cell infiltration profile with aging. In conclusion, we have established syngeneic tumor models using aged mice and found aged mice exhibit higher toxicity against drugs while the effect of aging on tumor growth kinetics varies depending on models. Differences in immune cell infiltration in the tumor might be an underlying event that causes age-related differences in response to anti-PD1 treatment. The integration of aging in cancer research could potentially bridge the gap between preclinical studies and clinical outcomes.

Citation Format: Jiwon Yang, Andrew Schile, Mingshan Cheng, James Keck. Age-related cancer drug toxicity and efficacy, and immune modulation in C57BL6J syngeneic model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2749.