39P - Efficacy of Tumor Treating Fields (TTFields) and anti-PD-1 in non-small cell lung cancer (NSCLC) preclinical models

Abstract

Background: Tumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via non-invasive application of low intensity, intermediate frequency, alternating electric fields. TTFields is approved for the treatment of both newly diagnosed and recurrent glioblastoma. TTFields interrupt mitosis in cancer cells by disrupting microtubules and septin filaments, which play key roles in mitosis. The mitotic effects of TTFields include abnormal chromosome segregation that trigger different forms of cell death. We evaluated TTFields’ effect on immunogenic cell death and its efficacy when combined with an immune checkpoint inhibitor (αPD1) in NSCLC. Methods: Murine Lewis lung carcinoma (LLC) cells were treated with TTFields using the inovitroTM system. Levels of cell surface calreticulin (CRT) and intracellular ATP levels were evaluated using flow cytometry. High mobility group box 1 (HMGB1) secretion was measured using an ELISA assay. Mice inoculated with LLC cells were treated with isotype control, TTFields, αPD-1, or TTFields + αPD-1. Tumor volume monitoring and intra-tumor immune cell profiling were performed. Results: TTFields induced elevated cell surface expression of CRT, decreased ATP levels, and promoted HMGB1 secretion. In vivo, the combined treatment of TTFields + α-PD-1 led to a significant decrease in lung tumor volume compared to all three other groups (P < 0.001). Significant increase in CD45+ tumor infiltrating cells was observed in the TTFields + αPD-1-treated mice. Infiltrating cells demonstrated a significant upregulation of surface PD-L1 expression. Both F4/80+CD11b+ cells and CD11c+ cells exhibited higher tumor infiltration and elevated PD-L1 expression, as compared to the control group. These findings indicate enhanced inflammatory antitumor environment conferred by the combination of TTFields + αPD-1. Conclusions: Our results demonstrate that TTFields treatment potentiates immunogenic cell death in NSCLC cancer cells. Combining TTFields with specific immunotherapies such as anti-PD-1 may enhance antitumor immunity and result in increased tumor control. A phase III clinical study on TTFields in combination with either PD-1 inhibitors or docetaxel in NSCLC is underway. Legal entity responsible for the study: Novocure Ltd Funding: Novocure Ltd Disclosure: U. Weinberg: Full time employee of Novocure. T. Voloshin, O.T. Yitzaki, N. Kaynan, M. Giladi, A. Shteingauz, M. Munster, S. Cahal, E.D. Kirson: Full time employee of Novocure Ltd. Y. Palti: Shareholder at Novocure Ltd, NY.