Abstract B034: Efficacy of Tumor Treating Fields (TTFields) together with gemcitabine and nab-paclitaxel (Gem/NabP) for treatment of pancreatic cancer, in vitro and in vivo

Abstract Background: Despite the use of intensive chemotherapy regimens such as FOLFIRINOX or gemcitabine combined with nab-paclitaxel (Gem/NabP), pancreatic cancer remains a major health challenge with poor treatment outcomes. Tumor Treating Fields (TTFields) therapy, a cancer treatment based on the application of electric fields that disrupt cellular processes crucial for cancer cell viability, is approved for treatment of glioblastoma, pleural mesothelioma, and non-small cell lung cancer (NSCLC). Recently, a significant increase in overall survival was demonstrated in a phase 3 study in patients with locally advanced pancreatic cancer treated with TTFields concomitant with Gem/NabP. TTFields have also been shown to induce immunogenic cell death (ICD) in cancer cells, elicit a systemic anti-cancer immune response in animal models of lung cancer, and to provide clinical benefit in patients with NSCLC when applied together with immune checkpoint inhibitors (ICI). The current study aimed to investigate the therapeutic potential of applying TTFields together with Gem/NabP in pancreatic cancer preclinical models and examine the involvement of a TTFields-induced immune response. Methods: Human AsPC-1 and BxPC-3, and mouse Panc02 pancreatic cancer cells were treated with TTFields (150 kHz, 1. 62 V/cm RMS), using the inovitro device. Cells treated for 48 hours were examined by RNA sequencing. Cells treated for 72 hours were analyzed for c-Myc expression, cell count, apoptosis, and the ICD markers: ATP depletion (quinacrine staining), surface calreticulin exposure, and HMGB1 release (Homogeneous Time Resolved Fluorescence (HTRF) technique). In vivo, immunocompetent C57Bl/6 mice were inoculated orthotopically with Panc02 cells. The mice were randomized into four groups: control, TTFields, Gem/NabP, and Gem/NabP + TTFields. TTFields were applied continuously for 10 days using the inovivo device, and the drugs (50 mg/kg for each) were injected i. p. once a week for a total of two administrations. At treatment end, tumors were measured using a caliper and then processed as a single-cell suspension for flow cytometry-based immunophenotyping. Blood was collected for immunophenotyping and examination of circulating levels of HMGB1. Results: TTFields downregulated the expression of c-Myc and associated downstream pathways, alone and when applied concomitant with Gem/NabP. The concomitant treatment enhanced cytotoxicity and promoted ICD in pancreatic cancer cells. In vivo, TTFields concomitant with Gem/NabP significantly reduced tumor volume compared to all other treatment groups and modulated tumor-associated and systemic immune profiles. Conclusions: This study demonstrates that TTFields have the potential to enhance the therapeutic efficacy of standard-of-care chemotherapy for pancreatic cancer by downregulating c-Myc expression, inducing immunogenic cell death, and reshaping the tumor immune microenvironment towards a more immune-inflamed phenotype. 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 Weingberg, Yoram Palti. Efficacy of Tumor Treating Fields (TTFields) together with gemcitabine and nab-paclitaxel (Gem/NabP) for treatment of pancreatic cancer, in vitro and in vivo abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B034.