Abstract 279: Bexarotene increases tumor CD8+ T cells and improves response to conventional breast chemotherapy in the transgenic mouse mammary tumor model TgMMTV-neu
Authors: Stanton Sasha E. , Gadd Ekram , Marzbani Edmond , Rastetter Lauren , Disis Mary L. 
Published: August 2015

Abstract
In breast cancer, increased immune infiltrate prior to neoadjuvant chemotherapy predicts improved pathologic complete response (pCR) and improved survival, however almost half of breast tumors have no CD8+ T cell infiltrate. Evidence has emerged that conventional breast cancer chemotherapy can increase CD8+ T cells (doxorubicin) and decrease the immunosuppressive regulatory CD4+ T cells (paclitaxel and cyclophosphamide); therefore discovering well tolerated agents that further enhance the anti-tumor immune function of these chemotherapies may further improve response in breast cancer patients. The oral agent bexarotene (a retinoic receptor agonist) showed a 20% disease response as a single agent in metastatic breast cancer and has been shown to increase CD8+ T cell tumor infiltration and decrease CD8+ T cell apoptosis in vitro. The goal of this study is to demonstrate whether this well tolerated oral agent can enhance the anti-tumor response of conventional chemotherapy through increasing intratumoral CD8+ T cells in TgMMTV-neu transgenic mice that are immunologically competent and genetically similar to human luminal B breast cancer.
Two of the most active chemotherapies in human breast cancer, doxorubicin and paclitaxel, each could inhibit tumor growth by 70-80% and increase CD8+ T cell tumor infiltrate by approximately 40% in tumor bearing TgMMTV-neu mice, a third breast cancer chemotherapy cyclophosphamide increased CD8+ tumor infiltrate by 45% (p = 0.011) but did not show a statistically significant decrease in tumor volume. When TgMMTV-neu mice with ∼100 mm3 tumors were treated with 50 mg/m2 bexarotene for four weeks they demonstrated a 44% increase in CD8+ tumor infiltrate (p = 0.05) and 60% decrease in mean tumor growth (p = 0.03) compared to control. However, the addition of bexarotene to chemotherapy was superior to chemotherapy alone, and significantly more effective than bexarotene alone. This enhanced anti-tumor function was even seen with cyclophosphamide that by itself had not inhibited tumor growth. Adding bexarotene to weekly doxorubicin decreased tumor growth by 98% (p = 0.008 compared to doxorubicin alone), adding bexarotene to weekly paclitaxel decreased tumor growth by 86% (p = 0.02 compared to paclitaxel alone), and adding bexarotene to weekly cyclophosphamide inhibited tumor growth by 82% (p = 0.04 compared to cyclophosphamide alone). Further studies are now ongoing to identify the anti-tumor role of bexarotene particularly its immune modulatory role. These results suggest that the addition of bexarotene, a relatively well-tolerated oral agent, may modify the immune environment and improve tumor response to chemotherapy in breast cancer possibly improving response to neoadjuvant chemotherapy.
Citation Format: Sasha E. Stanton, Ekram Gadd, Edmond Marzbani, Lauren Rastetter, Mary L. Disis. Bexarotene increases tumor CD8+ T cells and improves response to conventional breast chemotherapy in the transgenic mouse mammary tumor model TgMMTV-neu. [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 279. doi:10.1158/1538-7445.AM2015-279