Tumour treating fields therapy for glioblastoma: current advances and future directions

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and continues to portend poor survival, despite multimodal treatment using surgery and chemoradiotherapy. The addition of tumour-treating fields (TTFields)-an approach in which alternating electrical fields exert biophysical force on charged and polarisable molecules known as dipoles-to standard therapy, has been shown to extend survival for patients with newly diagnosed GBM, recurrent GBM and mesothelioma, leading to the clinical approval of this approach by the FDA. TTFields represent a non-invasive anticancer modality consisting of low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz), alternating electric fields delivered via cutaneous transducer arrays configured to provide optimal tumour-site coverage. Although TTFields were initially demonstrated to inhibit cancer cell proliferation by interfering with mitotic apparatus, it is becoming increasingly clear that TTFields show a broad mechanism of action by disrupting a multitude of biological processes, including DNA repair, cell permeability and immunological responses, to elicit therapeutic effects. This review describes advances in our current understanding of the mechanisms by which TTFields mediate anticancer effects. Additionally, we summarise the landscape of TTFields clinical trials across various cancers and consider how emerging preclinical data might inform future clinical applications for TTFields.

Fig. 1. Historical timeline of the emergence of TTFields as novel therapy for GBM patients.

In 2004, the first paper demonstrating the anticancer effects of TTFields in vitro and in vivo was published. Following these promising preclinical data, a number of clinical trials investigating the safety and efficacy of TTFields for the treatment of GBM were completed (details described at each relevant date), leading to the approval in 2011 and 2015 of TTFields for the treatment of recurrent and newly diagnosed GBM, respectively.

Fig. 2. The Optune system.

Left: the Optune TTFields delivery system consists of four transducer arrays, a field generator and a power source. Right: a patient wearing the Optune system. Images taken from Novocure, 2020.

Fig. 3. Summary of the mechanisms of action of TTFields.

Low-intensity, intermediate-frequency, alternating electrical fields exert biophysical forces on a variety of charged and polarisable molecules to elicit a spectrum of biological effects. A Antimitotic effects: during metaphase, the electric fields are uniform, causing dipolar molecules, such as tubulin, to align with the field. TTFields therefore interfere with tubulin polymerisation and depolymerisation during metaphase. At anaphase, TTFields prevent localisation of septin proteins to the mitotic spindle and inhibit assembly of the septin complex into a ring structure at the cleavage furrow. During cytokinesis, the electric fields are non-uniform, with the fields converging on the cleavage furrow, where the field intensity is the highest. As a result, strong dielectric force is applied on polarisable objects, pushing them towards the high-intensity region. Together, these effects result in abnormal chromosome segregation and/or cell death. B DNA repair. TTFields have been shown to downregulate BRCA and Fanconi anaemia (FA) pathway genes, which have been associated with increased replication stress and increased double-strand break (DSB) formation. Additionally, homologous recombination repair (HRR) is impaired by TTFields, resulting in reduced efficiency of DSB repair. C Autophagy. TTFields have been suggested to prevent the inhibitory effects of the PI3K/Akt/mTORC1 signalling pathway on autophagy, resulting in increased activation of autophagy with TTFields therapy. Further studies are needed to ascertain whether autophagy is activated as a cell survival or cell death signal in response to TTFields. D Antitumour immunity. TTFields stimulates macrophages (Mø) to secrete reactive oxygen species (ROS), nitric oxide (NO) and proinflammatory cytokines such as interleukin (IL)-1β, tumour necrosis factor (TNF)-α and IL-6. Additionally, TTFields promote immunogenic cell death via dendritic cell (DC) recruitment and maturation (mat), ultimately leading to an increase in the accumulation of CD4 + and CD8 + T cells at the tumour site. The combination of TTFields with anti-PD-1 therapy might enhance PD-L1 expression in infiltrating DCs and macrophages to further enhance antitumour immunity. E Anti-migratory. TTFields reduce the capacity of cancer cells for migration and invasion through nuclear factor (NF)-κB-, mitogen-activated protein kinase (MAPK)- and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent mechanisms. F Cell membrane permeability. TTFields increase cell membrane permeability by increasing the number and size of holes in the cell membrane, thereby potentially enhancing sensitivity to chemotherapeutic drugs.