Kim, Pan, and Soares et al. treated GVAX (irradiated whole-cell vaccine) with DNA methyltransferase inhibitor decitabine (DAC) to develop EpiGVAX – an epigenetically regulated cancer vaccine. Treatment of murine colorectal cancer (CRC) cell line CT26 with DAC increased the expression of several cancer-testis antigens (CTA) along with a new CTA Tra-P1A. In a CT26 liver metastatic tumor model, one cycle of vaccination with EpiGVAX plus systemic treatment with DAC induced the expansion of Tra-P1A antigen-specific CD8+ T cells and demonstrated improved survival outcome over GVAX.
Contributed by Shishir Pant
ABSTRACT: Metastatic colorectal cancer (CRC) is poorly immunogenic, with limited neoantigens that can be targeted by cancer vaccine. Previous approaches to upregulate neoantigen have had limited success. In this study, we investigated the role of a DNA methyltransferase inhibitor (DNMTi), 5-aza-2'-deoxycytidine (DAC), in inducing cancer testis antigen (CTA) expression and evaluated the antitumor efficacy of a combinatorial approach with an epigenetically regulated cancer vaccine EpiGVAX and DAC. A murine model of metastatic CRC treated with combination therapy with an irradiated whole-cell CRC vaccine (GVAX) and DAC was used to assess the antitumor efficacy. DAC significantly induced expression of CTAs in CRC, including a new CTA Tra-P1A with a known neoepitope, P1A. Epigenetically modified EpiGVAX with DAC improved survival outcomes of GVAX. Using the epigenetically regulated antigen Tra-P1A as an example, our study suggests that the improved efficacy of EpiGVAX with DAC may due in part to the enhanced antigen-specific antitumor immune responses. This study shows that epigenetic therapy with DNMTi can not only induce new CTA expression but may also sensitize tumor cells for immunotherapy. Neoantigen-based EpiGVAX combined with DAC can improve the antitumor efficacy of GVAX by inducing antigen-specific antitumor T cell responses to epigenetically regulated proteins.