Abstract P4-04-16: Characterization of an autologous tumor cell vaccine against breast cancer in mice

Abstract

Abstract The vast majority of breast cancer-related deaths are due to progressive recurrences of non-metastatic disease. Current adjuvant therapies aimed at preventing breast cancer recurrence are ineffective for tens of thousands of women each year. In addition, current adjuvant therapies carry significant co-morbidities. Active, specific immune-based strategies have the potential to train a patient's immune system to recognize and eliminate occult metastases. Here, we explore autologous tumor cell vaccines (ATCVs) as a strategy to prevent tumor recurrence and improve survival. Because >90% of breast cancer patients undergo resection, autologous tumor cells are readily available for the production of personalized vaccine. Patient-specific vaccination is particularly attractive for breast cancer which is highly heterogeneous. The major disadvantage of ATCVs, is poor immunogenicity. Thus, in order to develop an effective, immunogenic ATCV against breast cancer, we wanted to understand the features of immunogenicity. In this study, we evaluated the immunogenicities of two murine breast cancer cell lines, EMT6 and 4T1. For tumor protection studies, BALB/c female mice were given priming and booster vaccinations, ten days apart, with 1,000,000 irradiated (100Gy) cells. Ten days after the booster vaccination, mice were challenged with live tumor cells. Mice vaccinated with EMT6 cells were completely protected against a live EMT6 challenge in 80% of mice. However, mice vaccinated with irradiated 4T1 cells failed to provide any protection against a live 4T1 challenge. Most interestingly, when mice were vaccinated with a mixture of irradiated EMT6 and 4T1 cells, the protective response against EMT6 challenge was significantly diminished as 60% of mice developed tumors. This finding implied that non-immunogenic 4T1 cells released one or more immunosuppressive factors that inhibited anti-EMT6 immunity. Thus, we investigated the levels of different immunosuppressive cytokines, GM-CSF, IL-6, MCP-1, TGF-β and VEGF released by both 4T1 and EMT6 cells before and after irradiation. Of the different cytokines measured, we found that only GM-CSF is produced at significantly higher levels by 4T1 cells than EMT6 cells. Since at higher levels (>200pg/ml) GM-CSF can induce the accumulation of large amounts of myeloid derived suppressor cells (MDSCs) in the tumor site and lymphoid organs, we believe it to be the reason for the failure of the hybrid vaccine. Future studies will determine if blocking GM-CSF production by 4T1 cells will decrease the accumulation of MDSCs and subsequently increase anti-tumor immunity. Citation Format: Ravindranathan S, Kurtz SL, Smith SG, Koppolu B, Nguyen KG, Zaharoff DA. Characterization of an autologous tumor cell vaccine against breast cancer in mice. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-16.