Abstract A33: The next-generation BET inhibitor, PLX51107, delays melanoma growth, altering the tumor immune microenvironment via Cox2 inhibition

Epigenetic agents such as bromodomain and extra terminal domain inhibitors (BETi) slow tumor growth via tumor intrinsic alterations; however, their effects on antitumor immunity remain unclear. A recent advance is the development of next-generation BETi that are potent and display a favorable half-life. Here, we tested the next-generation BETi, PLX51107, for immune-based effects on tumor growth in BRAF V600E melanoma syngeneic models. PLX51107 delayed melanoma tumor growth to differing degrees and altered the immunogenicity by lowering PD-L1 and FasL and increasing MHC-I in highly responsive melanomas. Moreover, PLX51107 treatment increased activated, proliferating and functional CD8+ T cells in tumors, leading to CD8+ T-mediated tumor growth delay. PLX51107 led to increased CD8-promoting, antitumor dendritic cells by acting as a Cox2 inhibitor. The accumulation of CSF-1R+ tumor-associated macrophages in poorly responsive melanoma limited PLX51107 efficacy. Importantly, PLX51107 delayed the growth of tumors that progressed on anti-PD-1 therapy, a response associated with decreased Cox2 levels, decreased PD-L1 expression and increased MHC-I expression on nonhematopoietic cells and increased intratumoral CD8+ T cells. Thus, next-generation BETi represent a potential first-line and secondary treatment strategy for metastatic melanoma by eliciting effects, at least in part, on antitumor immunity. Citation Format: Dan A. Erkes, Conroy O. Field, Claudia Capparelli, Manoela Tiago, Timothy J. Purwin, Shea A. Heilman, Inna Chervoneva, Adam C. Berger, Sheera R. Rosenbaum, Edward J. Hartsough, Jessie Villanueva, Andrew E. Aplin. The next-generation BET inhibitor, PLX51107, delays melanoma growth, altering the tumor immune microenvironment via Cox2 inhibition [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A33.