Tumor Treating Fields – Behind and Beyond Inhibiting the Cancer Cell Cycle

2020 ◽  
Vol 19 (8) ◽  
pp. 599-610 ◽  
Author(s):  
Cédric Kissling ◽  
Stefano Di Santo
Keyword(s):  
Cancer Cell ◽  
Electric Fields ◽  
Unmet Need ◽  
Mechanisms Of Action ◽  
Treatment Modalities ◽  
Tumor Treating Fields ◽  
Precise Knowledge ◽  
Alternating Electric Fields ◽  
State Of Research ◽  
New Treatment

The unmet need for a safe treatment that significantly improves the overall survival, as well as the quality of life of patients with brain tumors, has urged researchers to work out new treatment modalities. About 15 years ago, it was shown that alternating electric fields significantly impair the growth of cancer cells. Recently, this potentially revolutionary approach called Tumor Treating Fields (TTFs) has been FDA-approved for the treatment of glioblastoma as well as mesothelioma. However, despite the promising reports on the potential of TTFs, the precise knowledge of the mechanisms of action is still lacking. The purpose of this review is, thus, to present the current state of research and to highlight the variety of ultrastructural effects of TTFs. Moreover, the aim is to bring to the foreground less discussed mechanisms of action of TTFs, which might develop into novel therapeutic approaches. Therefore, a systematic literature search in Ovid Medline and Embase was performed on clinical and preclinical data concerning TTFs. The alternating electric fields force cellular components to aberrant dynamics, among which the most evident is the inhibition of the mitotic spindle assembly leading to impaired cancer cell division and cell death. However, a variety of other microstructural events induced by TTFs, such as inhibition of DNA repair and cell migration, as well as an enhancement of anti- tumor immune response and membrane permeability, have been reported. In addition, apart from a suggested interference with angiogenesis, no TTF-induced effects on normal cells have been described so far.

scholarly journals Patient Experiences of Postinfectious Olfactory Dysfunction

ORL ◽  
2021 ◽  
pp. 1-5
Author(s):  
Carl M Philpott ◽  
James Boardman ◽  
Duncan Boak
Keyword(s):  
Online Survey ◽  
Unmet Need ◽  
Olfactory Dysfunction ◽  
Treatment Modalities ◽  
Medical Practitioners ◽  
Clinical Trials Unit ◽  
New Treatment ◽  
The Uk ◽  
Patients Experience ◽  
Age Range

<b><i>Introduction:</i></b> To highlight the importance of the need for new treatment modalities, this study aimed to characterise the experience of patients with postinfectious olfactory dysfunction (PIOD) in terms of the treatment they received. <b><i>Methods:</i></b> An online survey was hosted by the Norwich Clinical Trials Unit on the secure REDCap server. Members of the charity Fifth Sense (the UK charity that represents and supports people affected by smell and taste disorders) were invited to participate. <b><i>Results:</i></b> There were 149 respondents, of whom 127 had identified themselves as having (or had) PIOD. The age range of respondents to the survey was 28–85 years, with a mean of 58 ± 12 years, with the duration of their disorder &#x3c;5 years in 63% of cases. Respondents reported experiencing variable treatment with oral and/or intranasal steroids given typically (28%), often with no benefit, but with 50% receiving no treatment whatsoever; only 3% reported undertaking olfactory training. Over two-thirds of patients experience parosmia and, up to 5 years from the onset of the problem, were still actively seeking a solution. <b><i>Conclusion:</i></b> There appears to be a need to encourage greater use of guidelines for olfactory disorders amongst medical practitioners and also to develop more effective treatments for patients with PIOD, where there is clearly an unmet need.

scholarly journals Tumor treating fields in the management of Glioblastoma: opportunities for advanced imaging

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Vikram S. Soni ◽  
Ted K. Yanagihara
Keyword(s):  
Clinical Trials ◽  
Cancer Therapy ◽  
Electric Fields ◽  
Randomized Clinical Trials ◽  
Phase Iii ◽  
Imaging Biomarkers ◽  
Tumor Treating Fields ◽  
Alternating Electric Fields ◽  
Promising Line

AbstractAlternating electric fields have been successfully applied to cancer cells in-vitro to disrupt malignant progression and this antimitotic therapy has now been proven to be efficacious in Phase II and Phase III randomized clinical trials of patients with glioblastoma. With additional clinical trials ongoing in a number of other malignancies, there is a crucial need for a better understanding of the radiographic predictors of response and standardization of surveillance imaging interpretation. However, many radiologists have yet to become familiarized with this emerging cancer therapy and there is little active investigation to develop prognostic or predictive imaging biomarkers. This article provides an overview of the pre-clinical data that elucidate the biologic mechanisms of alternating electric fields as a cancer therapy. Results from clinical trials in patients with glioblastoma are then reviewed while elaborating on the several limitations to adoption of this promising line of treatment. Finally, a proposal for the development of imaging markers as a means of overcoming some of these limitations is made, which may improve treatment utilization by augmenting patient selection not only in glioblastoma, but also other malignant conditions for which this therapy is currently being evaluated.

scholarly journals Multimodal Treatment in Glioblastomas

2021 ◽  
Author(s):  
Ercan Çetin ◽  
Serdar Kabataş
Keyword(s):  
Overall Survival ◽  
Multimodal Treatment ◽  
Poor Prognosis ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Modalities ◽  
Tumor Vaccines ◽  
Tumor Treating Fields ◽  
The Poor ◽  
New Treatment

Glioblastomas are the most common primary brain tumors. Despite aggressive resection, radiotherapy and concomitant chemotheraphy overall survival is 14-16 months, and 5 year survivial rate is only 2%. The poor prognosis required development of new treatment modalities. Tumor Treating Fields, molecularly targetted drugs, antiangiogenic molecules, immune checkpoint inhibitors, tumor vaccines, Chimeric Antigen Receptor-T cell, viral theraphy and oncolytic viruse and mesenchymal stem cell vectors are some of the modalities that are currently being developed.

Abstract 3543: Alternating electric fields (TTFields) induce autophagy in human cancer cell lines

2016 ◽  
Author(s):  
Yaara Porat ◽  
Anna Shteingauz ◽  
Moshe Giladi ◽  
Rosa S. Schneiderman ◽  
Tali Voloshin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Electric Fields ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Alternating Electric Fields

scholarly journals CTNI-73. OVERALL SURVIVAL OF NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS TREATED BY STANDARD THERAPY IN COMPARISON TO STANDARD THERAPY PLUS TUMOR TREATING FIELDS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii59-ii59
Author(s):  
Aaron Rulseh ◽  
Adam Derner ◽  
Jan Sroubek ◽  
Jan Klener ◽  
Josef Vymazal
Keyword(s):  
Overall Survival ◽  
Electric Fields ◽  
Standard Therapy ◽  
Intermediate Frequency ◽  
Microtubule Assembly ◽  
Control Group ◽  
Newly Diagnosed ◽  
Tumor Treating Fields ◽  
Alternating Electric Fields ◽  
Overall Survival Benefit

Abstract BACKGROUND Tumor treating fields (TTFields; 200 kHz) have shown significant prolonged survival in newly diagnosed (ndGBM). TTFields are anti-mitotic, low intensity, intermediate frequency alternating electric fields. The applied fields disrupt the mitotic spindle, microtubule assembly and the segregation of intracellular organelles during cell division, leading to apoptosis or mitotic arrest. We compared overall survival (OS) between patients recently treated with standard therapy and standard therapy plus TTFields at our institution. METHODS Subjects (N=25) with ndGBM treated with standard therapy plus TTFields (STDTh-TTF) at our institution were included. Standard therapy (STDTh) consisted of surgical resection, followed by combined radiotherapy and chemotherapy (Temozolomide). In 3 cases, biopsies were performed instead of resection. The date of resection or biopsy was considered the entry date and was used in calculating survival. The study took place from July 2015 to April 2019. A matching control group of 25 subjects with ndGBM were treated with STDTh alone at our institution and were assembled from our database based primarily on date of resection or biopsy, and secondarily by age (2 subjects underwent biopsy in place of resection). When assembling the control group, the investigators were blinded to survival outcome. RESULTS Significantly greater overall survival was observed for the group treated by TTFields in addition to standard therapy (p &lt; 0.001; Hazard ratio [HR] 0.21; 95% confidence interval [CI] 0.1–0.45; median survival time STDTh-TTF 31.7 months, STDTh 7.1 months). The groups were balanced with respect to sex, and no differences with respect to age (p = 0.13; STDTh-TTF mean 51.58 years, SD 8.8; STDTh mean 52.42 years, SD 8.7) or inclusion date (p = 0.22) by paired t-test were detected. CONCLUSIONS Our initial results appear promising with respect to overall survival benefit in patients undergoing TTFields treatment in addition to standard therapy.

scholarly journals CTNI-68. EFFICACY OF TTFIELDS IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM) – SUB-GROUP ANALYSIS OF THE EF-14 TRIAL

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii58-ii58
Author(s):  
Zvi Ram ◽  
Chae-Yong Kim ◽  
Jay-Jiguang Zhu
Keyword(s):  
Elderly Patients ◽  
Electric Fields ◽  
Group Analysis ◽  
Progression Free Survival ◽  
The Elderly ◽  
Underlying Disease ◽  
Newly Diagnosed ◽  
Serious Adverse Events ◽  
Tumor Treating Fields ◽  
Alternating Electric Fields

Abstract BACKGROUND Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment that utilizes low intensity alternating electric fields delivered non-invasively to the tumor using a portable medical device. In the EF-14 phase 3 study leading to FDA approval, TTFields significantly extended survival in newly diagnosed GBM when added to maintenance temozolomide (TMZ). Elderly GBM patients usually have worse prognosis and often receive only partial treatment for the disease. This sub-group analysis examined the effects of TTFields in the elderly population (≥65 years of age) enrolled in the EF-14 study. METHODS All 134 elderly patients (≥65 years of age) from the EF-14’s intent-to-treat population were included in the analysis, Overall survival (OS) and progression-free survival (PFS), as well as adverse event frequency and severity were compared between the TMZ/TTFields arm and the TMZ alone arm. RESULTS The median age was 69 (range: 65–83), median KPS was 90%, and 69% were male. Median PFS from randomization was 6.5 months versus 3.9 months in the TMZ/TTFields versus TMZ alone arms, respectively (hazard ratio [HR], 0.47 [95%CI 0.30, 0.74] P&lt; 0.0236). Median OS was 17.4 months versus 13.7 months in the TMZ/TTFields versus TMZ alone arm, respectively (HR 0.51 [CI 0.33, 0.77] P&lt; 0.020). Serious adverse events (SAEs) were reported in 39% of patients treated with TMZ/TTFields and in 33% of patients treated with TMZ alone. None of the SAEs were considered related to TTFields but attributed to TMZ or to the underlying disease. Grades 1–2 skin AEs related to TTFields were observed in 51% of patients. CONCLUSION Consistent with the overall outcome of the EF-14 study, elderly patients treated with TMZ/TTFields showed significantly better OS compared to patients on TMZ alone, and without increase in grade III or IV toxicity.

scholarly journals The Literature Review of Electricity Effects on Cell Physiology and Related New Electrical Treatment Modalities

2019 ◽  
Author(s):  
Ertunc Simdi ◽  
Kader Ozcan
Keyword(s):  
Literature Review ◽  
Electric Fields ◽  
Cell Biology ◽  
Experimental Studies ◽  
Low Frequency ◽  
Pulsed Electric Fields ◽  
Treatment Modalities ◽  
Cell Physiology ◽  
Extremely Low Frequency ◽  
New Treatment

This paper is a mini literature review about electromagnetic field&rsquo;s effects on cells, tissues and new treatment modalities. We have reviewed a papers which have been published in high quality journals in the last 5 years as two authors. This review&rsquo;s aim is to be a resource for experimental studies about electricity&rsquo;s effects on cell biology and pathophysiology. As a result of this literature review, we found that especially extremely low electric frequency and intermediate frequency fields have very important pathophysiological effects. We have mentioned four important expressions on this subject; electroporation, electrofusion, electrochemotherapy, gene electrotransference. Two different new treatment approaches have been developed by use of these two important electrical waves. First is tumor treating fields and the other is pulsed electric fields. Most studies in literature have been done with extremely low frequency and pulsed electric fields. In terms of diseases, most studies are about glioblastoma multiforme and malign melanoma.Most studies in literature have been done with extremely low frequency and pulsed electric fields. In terms of diseases, most studies are about glioblastoma and melanoma.

scholarly journals IMMU-42. DUAL ACTIVATION OF THE cGAS-STING PATHWAY AND AIM2-INDUCED PYROPTOSIS BY TUMOR-TREATING FIELDS PRODUCES ANTI-TUMOR IMMUNITY IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii113-ii114
Author(s):  
Dongjiang Chen ◽  
Mathew Sebastian ◽  
Tarun Hutchinson ◽  
Ashley Ghiaseddin ◽  
Sonisha Warren ◽  
...  
Keyword(s):  
Electric Fields ◽  
Tumor Immunity ◽  
Type I ◽  
Cervical Lymph Nodes ◽  
Tumor Treating Fields ◽  
Type I Ifns ◽  
Alternating Electric Fields ◽  
Dual Activation ◽  
Sting Pathway

Abstract OBJECTIVES Tumor Treating Fields (TTFields) was approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed Glioblastoma (GBM) patients and resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. In many patients, a transient stage of increased peritumoral edema is often observed early during TTFields treatment, suggesting that a major component of therapeutic efficacy by TTFields may be an immune mediated process. We hypothesize that TTFields activate the immune system by triggering pyroptosis and type I Interferon (IFN) response. METHODS A panel of GBM cell lines were treated with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system. Cells were analyzed for the production of micronuclei and activation of both pyroptosis and STING pathways using immunostaining, quantitative PCR, ELISA and cytometry. Pre-treated mouse GBM cells were injected into mouse brain to monitor survive and immunophenotyping. GBM patients’ blood was collected, and PBMC were isolated and analyzed by single cell RNAseq. RESULTS TTFields resulted in a significantly higher rate of micronuclei structures released into the cytoplasm, which were co-localized with two upstream dsDNA sensors AIM2 and cGAS. TTFields-activated micronuclei-dsDNA sensor complexes led to i) induction of pyroptotic cell death, as measured by LDH release assay, and through AIM2-recruited caspase1 activation and cleavage of pyroptosis-specific Gasdermin D; and ii) activation of STING pathway leading to the increase of type I IFNs and pro-inflammatory cytokines. In mouse model, double knocking down of STING/AIM2 eliminated the tumor suppression effects caused by TTFields. TTFields pretreated wild type cells successfully elevated dendritic cell level in mouse cervical lymph nodes which can be reversed by double knocking down. CONCLUSIONS These results provide compelling evidence that TTFields induces effective anti-tumor immunity in GBM cells and patients.

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