Abstract Immunotherapy has revolutionized cancer treatment across a range of malignancies, yet its efficacy in ovarian cancer (OC) has remained limited due to low tumor mutational burden and limited neoantigen availability. While current immunotherapy strategies have struggled to achieve durable responses, adoptive T cell therapy (ATT) combined with epigenetic therapies that expand the antigenic landscape present a promising avenue to overcome the inherent challenges of immune resistance in OC. Epigenetic remodeling can increase tumor immunogenicity as well as de-repress “cryptic antigens”, that are normally transcriptionally silent yet selectively expressed in malignant cells. These cryptic antigens arise from mis-splicing, alternative open reading frames, and endogenous retroelements that generate HLA-restricted peptides recognizable by T cells. Their selective expression in cancer cells and immunogenicity highlight the actionability of these non-canonical targets for immunotherapy. We treated four OC cell lines with DNA methyltransferase and histone deacetylase inhibitors and identified a reproducible subset of upregulated protein-coding cryptic antigens, including endogenous retroviruses (ERVs) and other endogenous retroelements. We then generated an overlapping peptide library spanning the identified targets to prime and expand T cells from PBMCs of healthy donors. The resultant T cell products demonstrated robust proliferation, antigen-specific cytokine production, and high-avidity responses across multiple peptide pools. Functional avidity assays confirmed specific recognition of epigenetically induced antigen targets. These results demonstrate that epigenetic therapy can uncover a previously inaccessible tumor-specific antigen pool in OC and enable the generation of potent T cell products directed against these cryptic antigens. Leveraging epigenetic induction of cryptic antigen expression may thus provide path a to expand the target landscape for ATT and improve therapeutic efficacy in ovarian cancer. Citation Format: Jose A. Colina, Katherine B. Chiappinelli, Erin E. Grundy, Conrad Russell Y. Cruz. Combination epigenetic therapy unmasks non-canonical neoantigens to improve adoptive T cell therapy in ovarian cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5626.
Colina et al. (2026) studied this question.