Abstract 3665: Tumor Treating Fields (TTFields) plus anti-PD-1 therapy induce immunogenic cell death resulting in enhanced antitumor efficacy

Abstract

Abstract Tumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. TTFields is approved for the treatment of both newly diagnosed and recurrent glioblastoma. TTFields interrupt cancer cell mitosis by disrupting microtubules and septin filaments, which play key roles in mitosis. The mitotic effects of TTFields include abnormal chromosome segregation and ER stress, which trigger different forms of cell death. We evaluated the in vitro and in vivo effects of TTFields combined with an immune checkpoint inhibitor (anti-PD1) on immunogenic cell death. Murine Lewis lung carcinoma (LLC) and ovarian surface epithelial (MOSE) cells were treated with TTFields using the inovitroTM system. Levels of calreticulin (CRT) on the surface of treated cells and intracellular ATP levels were evaluated using flow cytometry. High mobility group box 1 (HMGB1) secretion was measured using an ELISA assay. Mice were implanted with LLC cells were treated with TTFields, anti-PD-1, or a combination of the two modalities. Tumor volume was monitored; flow cytometry analysis was performed for phenotypic characterization of infiltrating immune cells. TTFields induced elevated cell surface expression of CRT, decreased intracellular ATP levels, and promoted HMGB1 secretion. In vivo, the combined treatment of lung tumor-bearing mice with TTFields plus anti-PD-1 led to a significant decrease in tumor volume compared to anti-PD-1 alone or to the control group. Significant increases in CD45+ tumor infiltrating cells were observed in the TTFields plus anti-PD-1 group. Infiltrating cells demonstrated a significant upregulation of surface PD-L1 expression. Both F4/80+CD11b+ cells and CS11c+ cells exhibited higher tumor infiltration and elevated PD-L1 expression as compared to infiltrating immune cell in the control group. Our results demonstrate that TTFields treatment potentiates immunogenic cell death in cancer cells. Combining TTFields with specific immunotherapies such as anti-PD-1 may enhance antitumor immunity and result in increased tumor control. Citation Format: Tali Voloshin, Orna Tal-Yitzhaki, Noa Kaynan, Moshe Giladi, Anna Shteingauz, Mijal Munster, Roni Blat, Yaara Porat, Rosa S. Schneiderman, Shay Cahal, Aviran Itzhaki, Eilon D. Kirson, Uri Weinberg, Yoram Palti. Tumor Treating Fields (TTFields) plus anti-PD-1 therapy induce immunogenic cell death resulting in enhanced antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3665. doi:10.1158/1538-7445.AM2017-3665