IMMU-59. ALTERNATING ELECTRIC FIELDS (TTFIELDs) INDUCE IMMUNOGENIC CELL DEATH RESULTING IN ENHANCED ANTITUMOR EFFICACY WHEN COMBINED WITH ANTI-PD-1 THERAPY

Abstract

AbstractTumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. TTFields are employed as a local treatment modality with the intent to kill tumor cells and reduce local recurrence. This therapy is approved for the treatment of patients with glioblastoma. Previous investigations have shown that TTFields disrupt formation of the mitotic spindle, leading to abnormal chromosome segregation and various modes of cell death. In this study we evaluated whether TTFields-induced cell death can be perceived as immunogenic by the immune system. We demonstrate that cancer cells that die under TTFields application exhibit release of the chromatin-binding protein high mobility group B1(HMGB-1), endoplasmic reticulum (ER) stress leading to Calreticulin translocation to the cell surface, and autophagy leading to decreased intracellular levels of adenosine triphosphate (ATP), all of which are cardinal signs of immunogenic cell death. In vivo, the combined treatment of lung tumor-bearing mice with TTFields plus the immune checkpoint inhibitor anti-programmed death 1 (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. These infiltrating cells, specifically macrophages (F4/80+CD11b+) and dendritic (CD11c+) cells, demonstrated a significant upregulation of surface PD-L1 expression as compared to infiltrating immune cells in the control group. Our results demonstrate the potential of TTFields therapy to induce immunogenic cell death in vitro which may lead enhanced immune response against cancer cells. We also demonstrate significant efficacy of concurrent application of TTFields and anti PD-1 therapy in vivo. These data suggest that combining TTFields with anti-PD-1 might achieve tumor control by further enhancing antitumor immunity.