Abstract P5-04-06: Oral immunomodulatory agents prevent tumor growth and increase tumor CD8 T cell infiltrate; bexarotene further improves tumor response to conventional chemotherapy in breast tumors
Authors: Stanton Sasha E , Gad Ekram , Marzbani Edmond , Rastetter Lauren , Disis Mary L 
Published: May 2015

Abstract
The tumor immune environment is important in breast cancer with greater than 50% immune infiltrate (LPBC) prior to neoadjuvant chemotherapy predicting improved pathologic complete response, and LPBC and CD8 infiltrate prior to adjuvant therapy predicting improved survival. Unfortunately, the majority of breast cancers do not have LPBC or robust CD8+ infiltrate. Evidence has emerged that conventional chemotherapy can increase CD8+ T cells therefore discovering ways to boost this response should further enhance the anti-tumor function. Three oral agents have modest anti-tumor function: metformin (oral biguanide), bexarotene (retinoic receptor agonist), and celecoxib (COX2 inhibitor). In vitro data suggest a role for these agents in increasing Th1 immunity: metformin was shown to increase MHC class I expression on tumor cells, bexarotene was shown to decrease CD8+ T cell apoptosis, and celecoxib has been shown to decrease MDSC cells. The goal of this study was to demonstrate whether addition of these oral agents to conventional chemotherapy enhanced the anti-tumor function of chemotherapy, possibly by modifying the immune environment in the transgenic mouse mammary tumor model TgMMTV-neu (genetically similar to luminal breast cancer).
Two active chemotherapies in human breast cancer, doxorubicin and paclitaxel, inhibited tumor growth and increased CD8+ T cell tumor infiltrate in transgenic mice. Treatment of mice with 100 mm3 tumors with doxorubicin (5 mg/kg weekly for four weeks) showed a 32% increase in CD8+ T cells and 85% decrease in tumor growth as compared to control mice (p=0.0001) and treatment with paclitaxel (10 mg/kg weekly for four weeks) showed a 40% increase in CD8+ tumor infiltrate (p=0.0068) and 60% decrease in tumor growth as compared to control treated mice (p=0.0026). A third chemotherapy cyclophosphamide (100 mg/kg weekly for four weeks) increased CD8+ tumor infiltrate by 45% (p=0.011) but did not show a significant decrease in tumor volume (p=0.57). Metformin and bexarotene also demonstrated increased CD8+ tumor infiltration and decreased breast tumor growth but celecoxib did not. Metformin treated mice had a 46% increase in CD8+ tumor infiltrate (p=0.001) and a 52% decrease in mean tumor volume (p=0.011) as compared to controls (75 mg/m2 of metformin for four weeks). Bexarotene treated mice had 44% increase in CD8+ tumor infiltrate (p=0.05) and 60% decrease in mean tumor growth (p=0.03) compared to control (treated with 50 mg/m2 bexarotene for four weeks). Of all three oral therapies, bexarotene was most effective inhibiting spontaneous tumor growth in the mice. Furthermore, addition of bexarotene to chemotherapy was superior to chemotherapy alone. 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). These results suggest that addition of bexarotene, a well-tolerated oral agent, to chemotherapy may improve tumor response in breast cancer.
Citation Format: Sasha E Stanton, Ekram Gad, Edmond Marzbani, Lauren Rastetter, Mary L Disis. Oral immunomodulatory agents prevent tumor growth and increase tumor CD8 T cell infiltrate; bexarotene further improves tumor response to conventional chemotherapy in breast tumors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-06.