Colormaps depicting the maximum TTFields intensity distributions in default layouts for brain tissue of a patient with pairs of transducer arrays positioned left-right (left) and anterior-posterior (right) in axial slices through the brain. TTFields, tumor treating fields. Image from Wenger C, et al. Improving tumor treating fields treatment efficacy in patients with glioblastoma using personalized array layouts. Int J Radiat Oncol Biol Phys. 2016;94(5):1137–43.
A published review paper funded by the University of Florida, Department of Neurosurgery documents how tumor treating fields – a non-ionizing electromagnetic exposure- tumor can act to treat glioma via several mechanisms of action. Treating fields (TTFields) are “a novel locoregional antineoplastic treatment modality utilizing low-intensity (1–3 V/cm), intermediate frequency (~ 100–500 kHz), alternating electric fields.” According to the paper, “TTFields target cancer cells by several mechanisms of action (MoA) including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects, and induction of apoptosis and immunogenic cell death. ”
Field intensities generated by TTFields within target tissues are low and do not generate any appreciable local heating , yet they are shown to have a range of biological effects, unrelated to substantial tissue heating.
Ghiaseddin AP, Shin D, Melnick K, Tran DD. Tumor Treating Fields in the Management of Patients with Malignant Gliomas. Curr Treat Options Oncol. 2020;21(9):76. Published 2020 Jul 30. doi:10.1007/s11864-020-00773-5
Abstract
Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a novel, locoregional, antineoplastic treatment modality with favorable efficacy and safety being demonstrated in the most aggressive type of malignant gliomas, glioblastoma (GBM). In 2 large randomized, controlled phase 3 trials, the addition of TTFields was associated with increased overall survival when combined with adjuvant temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM (ndGBM) and comparable overall survival compared with standard chemotherapy in patients with recurrent GBM (rGBM). TTFields target cancer cells by several mechanisms of action (MoA) including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects, and induction of apoptosis and immunogenic cell death. Having several MoAs makes TTFields an attractive modality to combine with standard, salvage, and novel treatment regimens (e.g., radiotherapy, chemotherapy, and immunotherapy). Treatment within the field of malignant gliomas is evolving to emphasize combinatorial approaches that work synergistically to improve patient outcomes. Here, we review the current use of TTFields in GBM, discuss MOA and treatment delivery, and consider the potential for its wider adoption in other gliomas.
Curr Treat Options Oncol. 2020; 21(9): 76.
Published online 2020 Jul 30. doi: 10.1007/s11864-020-00773-5
Excerpts
In rodent brains, TTFields induce temporary BBB disruption, lasting up to 96 h [47, 48]. These findings provide a potential new application for TTFields to enhance CNS delivery of small molecule BBB-impermeant pharmacological agents. Additionally, increased cell membrane permeability in GBM cells was shown to facilitate better uptake of intraoperative agents such as 5-aminolevulinic (5-ALA) used intraoperatively to delineate tumor-normal brain margins [48••]. Lastly, TTFields impair angiogenesis, a key process for tumor growth and progression, via VEGF-induced and hypoxia-inducible factor 1 alpha-regulated pathways [45], thus identifying potential synergism with anti-angiogenic agents (e.g., bevacizumab, cediranib, enzastaurin, and sunitinib) [49, 50].
“The potential for TTFields to permeabilize the BBB opens the door for combinations with systemic and targeted agents previously deemed unfeasible as anti-glioma modalities due to restricted brain access.”
“Effects of TTFields on cell migration and membrane integrity
TTFields have been shown to inhibit cell migration and invasion by inducing a more adhesive cell phenotype. This is achieved through dysregulation of cytoskeletal structures and proteins related to the epithelial-mesenchymal transition (e.g., actins, vimentin, and cadherin), potentially reducing the likelihood of recurrence or metastases [43,44,45,46]. TTFields also increase permeability of the plasma membrane in human GBM cells in vitro by triggering mislocalization of the tight junction proteins Claudin-5 and ZO-1 from the plasma membrane to the cytoplasm [47, 48]. Election microscopic images of the human GBM cell line U87-MG and murine astrocytoma cell line KR158B treated with TTFields for 1 h revealed a large number of perforations scattered throughout the plasma membrane [47, 48]. These perforations were large enough to allow for the uptake of fluorescently labeled dextran particles of up to 20 kDa in size. In rodent brains, TTFields induce temporary BBB disruption, lasting up to 96 h [47, 48]. These findings provide a potential new application for TTFields to enhance CNS delivery of small molecule BBB-impermeant pharmacological agents. Additionally, increased cell membrane permeability in GBM cells was shown to facilitate better uptake of intraoperative agents such as 5-aminolevulinic (5-ALA) used intraoperatively to delineate tumor-normal brain margins [48••]. Lastly, TTFields impair angiogenesis, a key process for tumor growth and progression, via VEGF-induced and hypoxia-inducible factor 1 alpha-regulated pathways [45], thus identifying potential synergism with anti-angiogenic agents (e.g., bevacizumab, cediranib, enzastaurin, and sunitinib) [49, 50].”
