Abstract P064: Dual effect of epigenetic inhibitor and CAR-NK cell therapy in bladder cancer

Abstract

Abstract Bladder cancer (BC) causes 220,000 deaths per year worldwide since current therapies cannot be used in a large proportion of patients due to comorbidities. Recently, new treatments have been developed, including immunotherapies aimed to induce an antitumor response by activating the patients' immune system. However, since those treatments are only effective in a small subset of patients, new therapies are needed. Epigenetic modifications are drivers of BC and their modulation by inhibitors is considered a promising approach for BC management. Moreover, these compounds also show immunomodulatory properties, including NK cells antitumor activities. We observed that novel inhibitor of epigenetic machinery CM-1758, against histone deacetylases, display growth inhibition in a variety of human BC cell lines (5637, RT112, 253J, J82 and TCCSUP) in the low micromolar range. In addition, the compound induced the surface expression of NK cell ligands (NKG2DLs) in four of these tumor cells as measured by flow cytometry. Furthermore, we developed chimeric antigen receptor (CAR)-NK cells that express high levels of CAR composed by a fusion of NKG2D receptor ectodomain with 4-1BB and CD3z. Cytotoxic effects of NKG2D CAR-NK cells in co-culture with BC tumor cells were significantly potentiated as compared with parental NK-92 cells. In particular, 253J cells treated with CM-1758, that augmented its NKG2DLs levels, increased their sensitivity to NKG2D CAR-NK cells in co-culture and this effect was dependent on NKG2D receptor. Our results support that treatment with epigenetic inhibitors may facilitate the use of CAR-NK-based cell therapies as a promising strategy for BC management. Citation Format: Lucia Morales, Sandra Pinto Nunes, Ester Munera-Maravilla, Jose Antonio Casado, Paula Río, Antonio Valeri, Edurne San José-Enériz, Xavier Agirre, Felipe Prosper, Jesús María Paramio. Dual effect of epigenetic inhibitor and CAR-NK cell therapy in bladder cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P064.