Abstract 2176: Tumor treating fields (TTFields) together with gemcitabine and nab-paclitaxel (Gem/NabP) are effective against pancreatic ductal adenocarcinoma (PDAC), in vitro and in vivo

Abstract Background: Tumor treating fields (TTFields) are a cancer therapy, approved for the treatment of glioblastoma, pleural mesothelioma, and non-small cell lung cancer (NSCLC). The efficacy and safety of TTFields concomitant with standard-of-care gemcitabine and nab-paclitaxel (Gem/NabP) are currently being tested in a phase 3 trial as front-line treatment for locally advanced pancreatic ductal adenocarcinoma (PDAC). TTFields are electric fields that disrupt critical cellular processes and induce immunogenic cell death (ICD) in cancer cells. They have also been shown to elicit a systemic anti-cancer immune response in animal models and to provide clinical benefit in patients with NSCLC when applied together with immune checkpoint inhibitors (ICI). The current study aimed to investigate the involvement of a TTFields-induced immune response in PDAC and the therapeutic potential of applying TTFields together with standard-of-care chemotherapies in preclinical models. Methods: Human BxPC-3 and AsPC-1, and mouse Panc02 (with stable luciferase expression) pancreatic cancer cells were treated with TTFields (150 kHz, 1.62 V/cm RMS) and examined for induction of apoptosis and ICD. The markers used to test ICD included ATP secretion, calreticulin surface exposure, and CD47expression. Panc02 cells were inoculated orthotopically into immunocompetent C57Bl/6 mice. The mice were randomized into four groups: control, TTFields, Gem/NabP, and Gem/NabP + TTFields. TTFields were applied continuously for 10 days, and the drugs were injected i.p. once a week for a total of two administrations at a concentration of 50 mg/kg for each drug. At the end of the treatment, tumor volume was measured using a caliper, after which the tumor was processed as a single-cell suspension for flow cytometry-based immunophenotyping. Blood was collected for immunophenotyping and examination of circulating levels of the ICD marker high mobility group box 1 protein (HMGB1). Results: TTFields application induced apoptosis and elicited ICD in all tested pancreatic cell lines. The latter was identified by ATP depletion, increased calreticulin surface exposure, and decreased CD47 expression. In vivo, TTFields concomitant with Gem/NabP significantly reduced tumor volume compared to all other treatment groups. TTFields treatment elevated the levels of HMGB1 and of effector CD8+ T cells in the peripheral blood. Conclusions: TTFields induce ICD and an antitumor immune response in PDAC and enhance the efficacy of standard-of-care chemotherapy for the treatment of PDAC in preclinical models. A phase 2 study evaluating the potential efficacy of TTFields together with Gem/NabP and ICI in metastatic PDAC is underway. Citation Format: Tal Kan, Tharwat Haj Khalil, Yiftah Barsheshet, Tali Voloshin, Avital Vorontsov, Boris Brant, Simona Zisman-Rozen, Lilach Koren, Roni Blatt, Shay Cahal, Catherine Tempel Brami, Sara Jacobovitch, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Tumor treating fields (TTFields) together with gemcitabine and nab-paclitaxel (Gem/NabP) are effective against pancreatic ductal adenocarcinoma (PDAC), in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2176.