scholarly journals Alternating electric tumor treating fields for treatment of glioblastoma: rationale, preclinical, and clinical studies

2018 ◽  
Vol 128 (2) ◽  
pp. 414-421 ◽  
Author(s):  
Sandeep Mittal ◽  
Neil V. Klinger ◽  
Sharon K. Michelhaugh ◽  
Geoffrey R. Barger ◽  
Susan C. Pannullo ◽  
...  
Keyword(s):  
Electric Fields ◽  
Clinical Data ◽  
Combined Treatment ◽  
Current Evidence ◽  
Newly Diagnosed ◽  
Tumor Treating Fields ◽  
Alternating Electric Fields ◽  
Recurrent Gbm

OBJECTIVETreatment for glioblastoma (GBM) remains largely unsuccessful, even with aggressive combined treatment via surgery, radiotherapy, and chemotherapy. Tumor treating fields (TTFs) are low-intensity, intermediate-frequency, alternating electric fields that have antiproliferative properties in vitro and in vivo. The authors provide an up-to-date review of the mechanism of action as well as preclinical and clinical data on TTFs.METHODSA systematic review of the literature was performed using the terms “tumor treating fields,” “alternating electric fields,” “glioblastoma,” “Optune,” “NovoTTF-100A,” and “Novocure.”RESULTSPreclinical and clinical data have demonstrated the potential efficacy of TTFs for treatment of GBM, leading to several pilot studies, clinical trials, and, in 2011, FDA approval for its use as salvage therapy for recurrent GBM and, in 2015, approval for newly diagnosed GBM.CONCLUSIONSCurrent evidence supports the use of TTFs as an efficacious, antimitotic treatment with minimal toxicity in patients with newly diagnosed and recurrent GBM. Additional studies are needed to further optimize patient selection, determine cost-effectiveness, and assess the full impact on quality of life.

scholarly journals Microbial Growth Inhibition by Alternating Electric Fields in Mice with Pseudomonas aeruginosa Lung Infection

2010 ◽  
Vol 54 (8) ◽  
pp. 3212-3218 ◽  
Author(s):  
Moshe Giladi ◽  
Yaara Porat ◽  
Alexandra Blatt ◽  
Esther Shmueli ◽  
Yoram Wasserman ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Growth Inhibition ◽  
Electric Fields ◽  
Bacterial Growth ◽  
Lung Infection ◽  
Alternating Electric Fields ◽  
Microbial Growth Inhibition ◽  
Bacterial Growth Inhibition

ABSTRACT High-frequency, low-intensity electric fields generated by insulated electrodes have previously been shown to inhibit bacterial growth in vitro. In the present study, we tested the effect of these antimicrobial fields (AMFields) on the development of lung infection caused by Pseudomonas aeruginosa in mice. We demonstrate that AMFields (10 MHz) significantly inhibit bacterial growth in vivo, both as a stand-alone treatment and in combination with ceftazidime. In addition, we show that peripheral (skin) heating of about 2°C can contribute to bacterial growth inhibition in the lungs of mice. We suggest that the combination of alternating electric fields, together with the heat produced during their application, may serve as a novel antibacterial treatment modality.

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.

In vitro and in vivo efficacy and safety of tumor treating fields (TTFields) and sorafenib combination in hepatocellular carcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 551-551
Author(s):  
Shiri Davidi ◽  
Catherine Tempel-Brami ◽  
Mijal Munster ◽  
Karnit Gotlib ◽  
Einav Zeevi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Group ◽  
Combination Treatment ◽  
Combined Treatment ◽  
Efficacy And Safety ◽  
Tumor Treating Fields ◽  
Clonogenic Potential ◽  
Hcc Cells

551 Background: Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Sorafenib (oral multikinase inhibitor) is approved in patients with advanced HCC, yet survival benefit is limited. Tumor Treating Fields (TTFields) are an effective, anti-neoplastic treatment modality delivered via noninvasive, low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. The study aim was to explore in vitro and in vivo effects of TTFields alone and combined with sorafenib for HCC treatment. Methods: HCC (HepG2 and Huh-7D12) cells were TTFields treated with at frequencies of 100-400 kHz for 72 hr using the inovitro system. Efficacy of TTFields and sorafenib combined treatment was tested at optimal frequency with various sorafenib concentrations. Cell counts, apoptosis induction, and clonogenic potential were determined. Healthy rats were used to assess safety of TTFields applied to the abdomen. N1S1 HCC cells were injected into the left hepatic lobe of Sprague Dawley rat; after 1 week, TTFields (1.2 V/cm) and sorafenib (10 mg/kg) were applied for 6 days. Tumor growth was evaluated using MRI. Results: The optimal TTFields frequency was 150 kHz in HepG2 and Huh-7D12 HCC cells. TTFields 150 kHz treatment (1.0 - 1.7 V/cm, 72 hr) led to cell count reductions (53-55%) and further decreases in clonogenic potential (65-69%). TTFields and sorafenib combination treatment led to a significant reduction in cell count (2-way ANOVA, P < 0.05) vs either treatment alone. Also, tumor growth was significantly reduced in the combined treatment group vs the control group (student t test, P < 0.01). Tumor volume (fold increase) in the combination treatment group (1.6) was significantly lower vs control (5.9, P < 0.0001), TTFields alone (3.3, P < 0.01), and sorafenib alone (2.3, P < 0.05) groups. Safety studies did not reveal any TTFields related adverse events with delivery to the rat abdomen. Conclusions: In vitro and in vivo data demonstrated efficacy and safety of TTFields in HCC; and improved efficacy in combination with sorafenib. A phase 2 study (HEPANOVA; NCT03606590) will explore the clinical potential of TTFields 150 kHz plus sorafenib.

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 CTNI-70. LONG-TERM SURVIVAL IN GLIOBLASTOMA PATIENTS AFTER TUMOR TREATING FIELDS (TTFIELDS) THERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii58-ii59
Author(s):  
Aaron Rulseh ◽  
Adam Derner ◽  
Jan Sroubek ◽  
Jan Klener ◽  
Josef Vymazal
Keyword(s):  
Electric Fields ◽  
Median Survival ◽  
Good Health ◽  
Intermediate Frequency ◽  
Continuous Treatment ◽  
Newly Diagnosed ◽  
Term Survival ◽  
Membrane Breakdown ◽  
Tumor Treating Fields ◽  
Recurrent Gbm

Abstract PURPOSE Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor and traditionally has a median survival of only 10 to 14 months, with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only 5 to 7 months with optimal therapy. Thus, advances in treatment that may improve survival in these patients are highly desirable. METHODS Tumor treating fields (TTFields) therapy (Novocure Ltd., Haifa, Israel) is an approved antimitotic treatment for patients with newly diagnosed and recurrent GBM. TTFields are low-intensity (1–3 V/cm), intermediate-frequency (100–300 kHz) alternating electric fields that selectively kill or arrest the growth of rapidly dividing cells by inhibiting the proper formation of the mitotic spindle and by causing rapid membrane breakdown during cytokinesis. RESULTS Our center was the first in the world to apply TTFields treatment to histologically proven GBM in a pilot study of 20 individuals (10 GBM and 10 RGBM) in 2004 and 2005, and 4 of the original 20 patients are still alive today (2 GBM, 2 RGBM), in good health and no longer receiving any treatment roughly 15 years (range 14.2–15.9 years) after initiating TTFields therapy, with no clinical or radiological evidence of recurrence. The diagnosis of GBM was confirmed in all patients in two independent laboratories. Two of the 4 surviving patients exhibited radiological signs of tumor growth initially, before the tumor regressed in size after a median of 4 months of continuous treatment. CONCLUSIONS Our results indicate that TTFields treatment may be remarkably successful for both newly diagnosed and recurrent GBM patients. We recommend that TTFields treatment should be applied for a sufficient amount of time, and that initial radiologic progression following treatment initiation should not be considered a reason to discontinue treatment.

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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