@article{169468f8f04048d0b3fd2512d84a06cd,
title = "Neoantigen-based EpiGVAX vaccine initiates antitumor immunity in colorectal cancer",
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.",
author = "Kim, {Victoria M.} and Xingyi Pan and Soares, {Kevin C.} and Azad, {Nilofer S.} and Nita Ahuja and Gamper, {Christopher J.} and Blair, {Alex B.} and Stephen Muth and Ding Ding and Ladle, {Brian H.} and Lei Zheng",
note = "Funding Information: Conflict of interest: LZ receives grant support from Bristol-Meyer Squibb, Merck, iTeos, Amgen, NovaRock, InxMed, and Halozyme and received the royalty for licensing GVAX to Aduro BioTech. LZ is a paid consultant for/ advisory board member for Biosion, Alphamab, NovaRock, Akrevia, Sound Biologics, Fusun Biopharmaceutical, Foundation Medicine, DataRevive, and Mingruzhiyao. LZ holds shares at Alphamab and Mingruzhiyao. NA receives grant support from Cepheid and Astex and has served as consultant to Ethicon. NA has licensed methylation biomarkers to Cepheid. Funding Information: This work was supported by The Zhang Family Gift Fund (to LZ) and the Susie{\textquoteright}s Cause Colon Cancer Foundation grant (to LZ), NIH grants R01 CA169702 and R01 CA197296 (to LZ), National Cancer Institute Specialized Programs of Research Excellence in Gastrointestinal Cancers grant P50 CA062924 (to LZ), and Sidney Kimmel Comprehensive Cancer Center grant P30 CA006973 (to LZ). This work was supported by National Cancer Institute Cancer Center Support Grant P30 CA006973 (Cancer Center Core Grant) (to BHL). This work was supported by the National Heart, Lung, and Blood Institute (1K08HL108346-01) (to CJG). We would like to thank Montana O{\textquoteright}Dell from Texas Tech University for providing assistance for this project. Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",
year = "2020",
month = may,
day = "7",
doi = "10.1172/jci.insight.136368",
language = "English (US)",
volume = "5",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "9",
}