Immunomodulatory effects of tumor treating fields (TTFields) on colon cancer models.

Medientyp: E-Artikel

Titel: Immunomodulatory effects of tumor treating fields (TTFields) on colon cancer models

Beteiligte: Voloshin, Tali; Kaynan, Noa; Davidi, Shiri; Porat, Yaara; Shteingauz, Anna; Munster, Mijal; Schneiderman, Rosa S; Tempel-Brami, Catherine; Zeevi, Einav; Gotlib, Karnit; Cahal, Shay; Giladi, Moshe; Kirson, Eilon D.; Weinberg, Uri; Kinzel, Adrian; Palti, Yoram

Erschienen: American Society of Clinical Oncology (ASCO), 2020

Sprache: Englisch

DOI: 10.1200/jco.2020.38.4_suppl.136

ISSN: 0732-183X; 1527-7755

Schlagwörter: Cancer Research ; Oncology

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Beschreibung: 136 Background: Tumor Treating Fields (TTFields) are clinically approved in glioblastoma and malignant pleural mesothelioma as an anti-mitotic treatment modality delivered via noninvasive application of low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. We evaluated whether TTFields (150 kHz) induced colon cancer cell death can be perceived as immunogenic and suitable for combination with anti-programmed cell death protein 1 (anti-PD-1; immune checkpoint inhibitor) therapy. Methods: Murine colorectal carcinoma cells (CT-26) were treated with TTFields using the inovitro system. Immunogenic cell death was evaluated by assessing changes in the levels of calreticulin (CRT) on the surface of treated cells, phosphorylation of eukaryotic translation initiation factor alpha (eIF2α), and secretion of ATP and high-mobility group box 1 (HMGB1). For in-vivo studies, CT-26 cells were subcutaneously implanted in BALB/c mice. The mice were treated with TTFields (150 kHz), anti-PD-1 (200 μg/mouse), or a combination of the 2 modalities. Tumor volume was monitored and flow cytometry analyses performed for phenotypic characterization of infiltrating immune cells. Results: We demonstrate that cancer cell death under TTFields application exhibited release of HMGB1, ATP secretion from cells, and ER stress leading to CRT translocation to the cell surface, all of which are signs of immunogenic cell death. The combined treatment of colon 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. We demonstrate significant increases in both CD8 and CD4 T-cells in tumors treated with combination therapy, and in CD8 in tumors treated with anti-PD-1 alone. Conclusions: Our results establish the potential of TTFields therapy to induce immunogenic cell death. We also demonstrate efficacy of concurrent application of TTFields and anti PD-1 therapy in mouse cancer models. These data suggest that TTFields plus anti-PD-1 combination treatment may achieve tumor control by further enhancing anti-tumor immunity.

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