Alternating Electric Fields (Tumor-Treating Fields Therapy) Can Improve Chemotherapy Treatment Efficacy in Non-Small Cell Lung Cancer Both In Vitro and In Vivo

Abstract

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Common treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, and, in recent years, the clinical management paradigm has evolved with the advent of targeted therapies. Despite such advances, the impact of systemic therapies for advanced disease remains modest, and as such, the prognosis for patients with NSCLC remains poor. Standard modalities are not without their respective toxicities and there is a clear need to improve both efficacy and safety for current management approaches. Tumor-treating fields (TTFields) are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death. We evaluated the effects of combining TTFields with standard chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo. Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition of TTFields to chemotherapy resulted in enhanced treatment efficacy across all cell lines. We investigated the response of Lewis lung carcinoma and KLN205 squamous cell carcinoma in mice treated with TTFields in combination with pemetrexed, cisplatin, or paclitaxel and compared these to the efficacy observed in mice exposed only to the single agents. Combining TTFields with these therapeutic agents enhanced treatment efficacy in comparison with the respective single agents and control groups in all animal models. Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC.

Tumor-Treating Fields: A Fourth Modality in Cancer Treatment

“…In the preclinical setting, TTFields (150 kHz) applied in vitro demonstrated an antiproliferative effect on pancreatic cancer cells with decreased long-term clonogenicity, significantly increased number of abnormal mitotic figures, and decreased G 2 -M cell population (27). Furthermore, in the PC1-0 hamster pancreatic cancer model, TTFields significantly reduced tumor volume with an increase in the frequency of abnormal mitotic events (58).…”

“…TTFields have been shown to exert their antimitotic effects in numerous preclinical models of solid tumors through the same mechanisms of action (4,5,23,25,32). The maximal cytotoxic effect on each cell type is achieved by fine-tuning the frequency of TTFields applied within the intermediate range (between 100 and 300 kHz), and appears to be inversely correlated with cell size (4,5,24,27). Because of the low toxicity and efficacy demonstrated in multiple clinical trials, TTFields have been tested in preclinical studies together with cytotoxic chemotherapy agents in an attempt to augment overall antitumor effects.…”

“…Such chemotherapies included microtubule inhibitors, nucleoside analogues, folate antimetabolites, alkylating agents, and immune checkpoint inhibitors, all leading to an additive cytotoxic effect when combined with TTFields. Taxanes have been demonstrated to act synergistically when combined with TTFields (25,27,32). In addition, in preclinical models, TTFields have been shown to expose calreticulin on cell surface in vitro, and to significantly decrease tumor volume when combined with an anti-programmed T cell death 1 (anti-PD-1), leading to a significant increase in the infiltration of antigenpresenting cells into the tumor (33,34).…”

“…This included both squamous and nonsquamous models (5,27).In Lewis lung carcinoma and KLN205 squamous cell carcinoma implanted mice, treatment with TTFields in combination with pemetrexed, cisplatin, or paclitaxel showed more pronounced efficacy compared with single agents (27).…”

“…Reproduced from Gera et al (18). to aneuploidy in daughter cells, and a subsequent decrease in clonogenic potential (5,17,23,(25)(26)(27)(28). Septin has a greater dipole moment than tubulin [2711 Debyes (23) vs. 1660 Debyes (29)].…”