Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors

Abstract

We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro. Using implanted electrodes, these fields were also shown to inhibit the growth of dermal tumors in mice. The present study extends these findings to additional cell lines [human breast carcinoma; MDA-MB-231, and human non-small-cell lung carcinoma (H1299)] and to animal tumor models (intradermal B16F1 melanoma and intracranial F-98 glioma) using external insulated electrodes. These findings led to the initiation of a pilot clinical trial of the effects of TTFields in 10 patients with recurrent glioblastoma (GBM). Median time to disease progression in these patients was 26.1 weeks and median overall survival was 62.2 weeks. These time to disease progression and OS values are more than double the reported medians of historical control patients. No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients. The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes. We conclude that TTFields are a safe and effective new treatment modality which effectively slows down tumor growth in vitro, in vivo and, as demonstrated here, in human cancer patients.

Conflict of interest statement

Conflict of interest statement: Y.P. has a minority holding in NovoCure Ltd. and is a member of the company board of directors; E.D.K., A.I., D.M., S.S.-S., Z.G., R.S., and Y.W. are employed in full or part by NovoCure Ltd.; and M.S. is a clinical trial consultant to NovoCure Ltd.

Figures

Fig. 1.

ac field distribution in and around quiescent (A) and dividing (B) cells. Inside quiescent cells, the field is uniform, and the oscillating electric forces result only in “vibration” of ions and dipoles (the forces associated with each half cycle are denoted white and gray arrows). In contrast, the nonuniform field within dividing cells (B) induces forces pushing all dipoles toward the furrow. Note that at frequencies of 0.1–1.0 MHz, the cell membrane impedance is relatively high, so only a small fraction of the currents penetrate the cells as seen from the density of lines.

Fig. 2.

Time, frequency, and intensity dependence of the effect of TTFields on cancer cell proliferation. (A) The number of cells in untreated cultures (filled symbols) as compared with cultures treated with TTFields (open symbols) for 24 h (1.75 V/cm for MDA-MB-231, F-98, and H1299 cells and 1.1 V/cm for B16F1 cells). (B) The relative change in number of cells after 24 h of treatment of different frequencies (same TTFields intensity). (C) The effect of 24 h of exposure to TTFields of increasing intensities (at optimal frequencies). ● and ○, B16F1; ■ and □, MDA-MB-231; ▴ and ▵, F-98; ♦ and ♢, H1299.

Fig. 3.

TTFields inhibition of the growth of intracranial glioma. (A) FEM simulations (using a three-dimensional mesh) of the distribution of TTFields intensity within a simplified rat brain model. (B and C) Exemplary T1 weighted coronal MRI sections (after IV injection of Gd-DTPA) of the heads of a control and a TTFields treated (200 kHz, two-directional TTFields) rat, respectively. In both examples, the section shown is that with the largest diameter tumor. Head simulations are 3.1 × 1.9 cm ellipsoid; skin thickness, 0.4 mm (σ = 0.00045 S/m; ε = 1,120); skull thickness, 1.1 mm (σ = 0.015 S/m; ε = 16); thickness of the CSF surrounding the brain, 0.5 mm (σ = 2 S/m; ε = 109); and brain itself has the properties of a uniforms white matter (σ = 0.15 S/m; ε = 3,200). The electrodes placed over a 0.5-mm layer of hydrogel. Note the almost uniform field intensity in most brain volume. (Scale bars, 1 cm.)

Fig. 4.

Efficacy of TTFields treatment in recurrent GBM. (A) TTP of treated patients (n = 10); median TTP is 26.1 weeks (dashed black line). (B) Kaplan–Meier OS curve for NovoTTF-100A treated patients (n = 10). The median OS in these patients is 62.2 weeks (black dashed line), and the 1-year survival rate is 67.5% (blue dashed line).

Fig. 5.

Exemplary T1-weighted, post contrast, MRI scans of recurrent GBM patients before (Left) and after (Right) TTFields treatment. (A) Complete response after 8 months of treatment. (B) Stable disease (10% reduction in contrast enhancing area) after 9 months of treatment.