Efficacy and immunogenic effects of Tumor Treating Fields ( <scp>TTFields</scp> ) in preclinical models of pancreatic ductal adenocarcinoma, with and without gemcitabine/nab‐paclitaxel

Tumor Treating Fields (TTFields) are an approved cancer therapy for glioblastoma (GBM), pleural mesothelioma, and non-small cell lung cancer (NSCLC). A recent phase 3 trial of TTFields therapy concomitant with standard-of-care gemcitabine and nab-paclitaxel (Gem/NabP) as a first-line treatment for unresectable, locally advanced pancreatic adenocarcinoma demonstrated a significant increase in overall survival. The current study evaluated the effects of TTFields in preclinical pancreatic ductal adenocarcinoma (PDAC) models. The vast majority of PDAC patients harbor KRAS mutations, which are associated with a more aggressive disease phenotype and increased therapy resistance, driven in part by overexpression of the key transcription factor c-Myc. In the current study, TTFields application significantly suppressed c-Myc expression and induced immunogenic cell death (ICD)-characterized by increased calreticulin cell-surface exposure, extracellular ATP secretion, and elevated HMGB1 release-in pancreatic cancer models. These effects were further enhanced when TTFields were applied concomitantly with Gem/NabP. Causality between c-Myc modulation and immune readouts was not established. In vivo, TTFields application induced a systemic immune response, evidenced by dendritic cell activation, increased effector memory T cells, and greater tumor leukocyte infiltration. TTFields concomitant with Gem/NabP significantly reduced tumor volume, decreased tumor monocytic myeloid-derived suppressor cells (M-MDSC), and increased the tumor lymphocyte-to-monocyte ratio (LMR) compared to all other treatment groups. These findings support the potential of TTFields to enhance therapeutic efficacy. Moreover, TTFields-induced tumor immunogenicity may enable combination strategies with immunotherapies. A phase 2 clinical trial investigating TTFields with Gem/NabP and immune checkpoint inhibitors (ICIs) for metastatic PDAC is currently underway.