Abstract LB-319: A novel cancer-testis antigen, BORIS-based vaccine delivered by dendritic cells is effective against metastatic disease

Abstract

Abstract Although broad clinical benefits of anti-tumor immunotherapy have not been demonstrated, the current data suggest such strategies could be beneficial if capable of inducing strong anti-cancer cellular immune responses. We report testing for the first time, the therapeutic efficacy of a dendritic cell (DC)-based immunotherapy strategy targeting a novel cancer testis (CT) antigen, Brother of Regulator of Imprinted Sites (BORIS), which is an epigenetically acting tumor promoting transcription factor expressed in various human and mouse cancer cells. In addition to therapeutic potency, we evaluated the cellular immune responses by assessing BORIS-specific CD4 T cell proliferation, T cell cytokine production both by intracellular cytokine staining and ELISpot analysis, and CTL responses. We evaluated the impact of this therapy on the development of metastatic disease, by analyzing the number of spontaneous clonogenic metastases after a 10-day culture of lung homogenates in presence of 6-thioguanine. The presence of CD4, CD8, Treg and myeloid derived suppressor cells (MDSCs) in the tumor and in the spleen was analyzed by flow cytometry. DC loaded with zink-finger deleted (mutated) BORIS vaccine (DC/mBORIS) was evaluated in the non-immunogenic, very aggressive and highly metastatic mouse model of 4T1 mammary carcinoma. Vaccination of mice after 4T1 tumor implantation inhibited tumor growth (18.75% mice remained tumor-free) and dramatically lowered number of spontaneous clonogenic metastases (50% mice remained metastases-free). Higher numbers of immune-effector CD4 and CD8 T cells infiltrated the tumors of vaccinated mice compared to control animals. Therapeutic vaccination with DC/mBORIS significantly decreased the numbers of MDSC infiltrating the tumor, but not splenic MDSC, likely associated with the effect of the immunotherapy on tumor burden rather than a direct effect on MDSCs. Currently, we are testing the suppressive activity of splenocytes from tumor-bearing mice as well as MDSC isolated from these splenocytes. These data suggest that mBORIS is an attractive target for immunotherapy having substantial efficacy in this highly aggressive tumor model when incorporated into a DC-based immunotherapy, and which may be enhanced even further in combination with agents to attenuate tumor-associated immune suppression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-319.