Effectiveness and Safety of Tumor Treating Fields (150 kHz) plus Cisplatin or Pemetrexed Combination in Mesothelioma: in Vitro and in Vivo Findings

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer linked to asbestos exposure with a poor prognosis and limited treatment options. Tumor Treating Fields (TTFields) are a noninvasive, antineoplastic treatment delivered locoregionally to the tumor bed via low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. TTFields are FDA-approved as a first line therapy with pemetrexed plus platinum-based agent for unresectable MPM. TTFields with this combination was evaluated in the phase 2 STELLAR clinical trial (Ceresoli et al, Lancet Oncology 2019) in patients with unresectable MPM, demonstrating a promising median overall survival of ∼18.2 months (vs ∼12 months; historical control) without increases in systemic toxicity. Utilizing in vitro and in vivo models, we investigated the effects of TTFields alone and in combination with cisplatin or pemetrexed in MPM. Using the inovitroTM system, cells from human MPM cell lines (NCI-H2052 and MSTO-211H) were treated at various frequencies of TTFields for 72 hours. The combined treatment of TTFields with cisplatin or pemetrexed was tested by applying TTFields at the 150 kHz optimal frequency with various concentrations of cisplatin (80–5120 nM) or pemetrexed (2–4096 nM). Cell counts, clonogenic potential, and apoptosis induction were determined. TTFields (150 kHz) were applied to Fisher rats with IL-45 intrapleural tumors cells for 8 days and to C57BL/6 mice with RN5 S.C. tumors for 7 days. Tumor volume was determined using MRI. To determine treatment safety, TTFields (2–3 V/cm) were applied to the torsos of Sprague-Dawley rats at 150 kHz for 2 weeks and all major internal organs were histologically compared. The optimal TTFields frequency was 150 kHz in both NCI-H2052 and MSTO-211H human MPM cell lines. TTFields (150 kHz; 1.1 V/cm) application for 72 hours led to a 45-51% reduction in cell counts and a 46-64% additional decrease in clonogenic potential. TTFields plus cisplatin or pemetrexed significantly reduced the cell count, the clonogenic potential and induced apoptosis versus each treatment alone (P <0.0001). Tumor volume was significantly decreased in the TTFields plus pemetrexed plus cisplatin combination group versus the control group in both tumor models. Histological analysis of major internal organs showed no increase in pathological findings when TTFields were applied to the rat torso. These in vitro and in vivo data demonstrate that the optimal TTFields frequency to inhibit MPM is 150 kHz. TTFields alone showed effectiveness and safety, and combined with cisplatin or pemetrexed demonstrated enhanced effectiveness with no increased safety concerns in the torso. Findings were consistent with efficacy and safety findings in the STELLAR trial.