Abstract PR12: Epigenetic reprograming promotes an immunogenic ovarian tumor microenvironment and synergizes with adoptive transfer of engineered T cells expressing NY-ESO-1 specific T cell receptors

The ability of the immune system to recognize and reject tumors is dependent on several factors that include the expression of immunogenic target antigens on tumor cells, generation of high frequencies of tumor antigen-specific T cells with potent effector function, and capacity to overcome several mechanisms by which tumors escape immune attack. The immunosuppressive environment in the tumor bearing host and at the tumor site restricts persistence and function of antigen-specific T cells, and represent a major obstacle to a durable adoptive engineered TCR (T-cell receptor) cell transfer immunotherapy. DNA demethylation agents have been shown to change immune gene signatures of tumor cells and activate the expression of suppressed tumor antigens by relieving promotor hyper-methylation. In the current study, we aim to determine the immunomodulatory activity of demethylation agents on both ovarian cancer cells and immune cell components in tumor microenvironment, and identify strategies to enhance adoptive T-cell transfer (ACT) immunotherapy in ovarian cancer models. Using a preclinical xenograft model, NY-ESO-1 negative ovarian cancer, OVCAR3, we investigated therapeutic effects of three HLA-A*02 restricted clones of NY-ESO-1 specific CD8 TCR gene-engineered T cells in combination with the demethylation agents decitabine and SGI-110. Demethylation agent treatment followed by ACT elicited synergistic antitumor responses, ranging from inhibition to regression of tumor growth, with curative effect in some animals. In the NY-ESO-1 negative OVCAR3 model, demethylation agents not only induced expression of NY-ESO-1 tumor antigen and MHC I and II, rendering the tumor visible for recognition by CD8 T cells, but also dramatically promoted persistence and accumulation of adoptively transferred T cells at tumor site, as well as reduction of suppressive myeloid cells in the tumor. To further optimize the therapeutic effect of NY-ESO-1 specific CD8 T cells, we explored the activity of TCR gene-engineered NY-ESO-1 specific CD4 T cells that directly recognize cancer cells in a MHC II-restricted manner, in combination with decitabine. We also demonstrated that decitabine rendered the tumor visible for recognition by NY-ESO-1 specific CD4 T cells leading to significant tumor inhibition, and improved persistency of CD4 T cells at peripheral and tumor sites. To maximize curative effect and durability of the therapy, we are currently investigating the immunomodulatory role of decitabine in combination with both CD8 and CD4 T cells specific to NY-ESO-1 in ovarian cancer. Our findings provide insights into novel modes of action of demethylation agents, and indicate that, with optimized therapeutic strategies, demethylation agents can dramatically augment efficacy of adoptive T-cell transfer immunotherapy and counter the immunosuppressive mechanisms in ovarian cancer models. This abstract is also being presented as Poster B34. Citation Format: Li Shen, Bob McGray, Anthony Miliotto, Ariel Francois, Cheryl Eppolito, Junko Matsuzaki, Takemasa Tsuji, Richard Koya, Adekunle Odunsi. Epigenetic reprograming promotes an immunogenic ovarian tumor microenvironment and synergizes with adoptive transfer of engineered T cells expressing NY-ESO-1 specific T cell receptors. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR12.