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  Lunch & Poster Display session (ID 58)

  • Event: ELCC 2019
  • Type: Poster Display session
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 4/11/2019, 12:30 - 13:00, Hall 1

  • 28976

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    7P - Immunomodulatory effects of Tumor Treating Fields (TTFields) on lung cancer models (ID 436)

    12:30 - 13:00  |  Author(s): Catherine Tempel Brami
    • Abstract
    • Slides

    Background
    

    Tumor Treating Fields (TTFields) are a clinically approved anti-mitotic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. In this study, we evaluated whether TTFields-induced cell death can be perceived as immunogenic.

    a9ded1e5ce5d75814730bb4caaf49419 Methods
    

    Human and murine lung carcinoma cell lines were treated with TTFields using the inovitro system. Immunogenic cell death was evaluated by changes in the levels of calreticulin (CRT) on the surface of treated cells, phosphorylation of the translation initiation factor eIF2α, and secretion of ATP and High mobility group box 1 (HMGB1). Activation of immune cells was evaluated using co-culture of bone marrow derived dendritic cells (DCs) with TTFields treated cells. For in-vivo studies, mice orthotopically implanted with lung tumors were treated with TTFields, the immune checkpoint inhibitor anti-PD-1 or a combination of the two modalities. Tumor volume was monitored and flow cytometry analysis was performed for phenotypic characterization of infiltrating immune cells.

    20c51b5f4e9aeb5334c90ff072e6f928 Results
    

    We demonstrate that cancer cells that died 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 cardinal signs of immunogenic cell death. TTFields treated cells promoted in vitro phagocytosis by DCs and DC maturation as well as initiation of inflammation in vivo. The combined treatment of lung tumor-bearing mice with TTFields plus the immune checkpoint inhibitor 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. These infiltrating cells demonstrated upregulation of surface PD-L1 expression. Correspondingly, cytotoxic T-cells isolated from these tumors showed higher levels of IFN-γ production relative to untreated mice.

    fd69c5cf902969e6fb71d043085ddee6 Conclusions
    

    Our results demonstrate the potential of TTFields therapy to induce immunogenic cell death and increase the efficacy of anti PD-1 therapy by further enhancing antitumor immunity.

    b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study
    

    Novocure Israel.

    213f68309caaa4ccc14d5f99789640ad Funding
    

    Novocure Israel.

    682889d0a1d3b50267a69346a750433d Disclosure
    

    U. Weinberg, T. Voloshin Sela, Y. Porat, M. Munster, R.S. Schneiderman, C. Tempel Brami, S. Cahal, M. Giladi, A. Kinzel, Y. Palti: Full time employee: Novocure Israel; Stock options, stocks: Novocure. N. Kaynan, S. Davidi, A. Shteingauz, K. Gotlib, E. Zeevi: Full time employee: Novocure Israel; Stock options: Novocure. E. Kirson: Full time employee: Novocure Israe; Stock options, stocks: Novocure; Senior leadership position: Novocure.

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