Abstract 475: Combinational treatment with MUC1 vaccine and Indomethacin reduces breast tumor burden via a COX-independent pathway.

Abstract

Abstract Introduction: While much advancement has been made in breast cancer treatment, metastatic breast cancer remains an incurable disease. The glycoprotein MUC1 is over-expressed and underglycosylated in over 90% of human breast tumors and 100% of metastatic lesions, and thus was ranked the second most targetable tumor antigen (TA) by NCI. Vaccines against TAs have several benefits, including the chance to eliminate metastatic lesions that express the TA. To this end, we have proposed vaccinating with peptides from the MUC1 protein core, which is only visible to the immune system on the tumor-associated form of the protein. We have previously shown that vaccination does elicit a MUC1-specific immune response that can only be functional if the immunosuppressive tumor microenvironment is blocked to allow efficient tumor cell killing. We investigated the effectiveness of MUC1 vaccination in combination with drugs known to inhibit immunosuppression. Methods: Mice that are transgenic for human MUC1 were orthotopically injected with syngenic breast cancer cells expressing human MUC1. Mice were vaccinated after palpable tumor formation three times in 10 day intervals. Previous work has shown that blocking the cyclooxygenase pathway (COX) resulted in an inhibition of immunosuppression. Thus we treated daily with following drugs in combination with the MUC1-vaccine therapy: Indomethacine (COX1/2 inhibitor), Celecoxib (COX2 inhibitor), 1-methyl tryptophan (IDO inhibitor), and AH6809 (EP2 receptor antagonist). Tumor volume was monitored every day by caliper measurements. Immune activation was measured via an IFN-γ ELISPOT assay using T cells from tumor-draining lymph nodes as responders and dendritic cells pulsed with the vaccinating peptides as simulators. Results: MUC1 vaccine therapy alone causes a slight reduction in tumor burden, although not significant, but does induce IFN-γ production from T cells, indicating immune cell activation. Only the combinational therapy of Vaccine + Indomethacin results in a significant reduction in tumor size. All drugs cause significantly higher levels of IFN-γ production from T cells compared to vaccine alone but no reduction in tumor burden. The combinational treatments of Vaccine + Indomethacine and Vaccine + Celecoxib reduce intra-tumoral PGE2 levels compared to vaccine alone. In a repeat experiment, we found that vaccine alone and indomethacin alone caused a slight reduction in tumor burden, but tumor burden was only significantly reduced when the therapy was given in combination. Conclusion: In this model, MUC1 vaccine efficacy can be enhanced when given in combination with Indomethacin. Since Indomethacin but not Celecoxib reduced tumor burden when given in combination with the MUC1 vaccine, we suggest that Indomethacin enhanced vaccine efficacy via a COX-independent pathway. Future experiments will explore this mechanism. Citation Format: Jennifer M. Curry, Dahlia M. Besmer, Lopamudra Das Roy, Priyanka Grover, Sritama Nath, Shanti Rao, Pinku Mukherjee. Combinational treatment with MUC1 vaccine and Indomethacin reduces breast tumor burden via a COX-independent pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 475. doi:10.1158/1538-7445.AM2013-475