Tumor Treating Fields Therapy Research Articles

Letter to the Editor: "Imperative for Increased Research into Tumor Treating Fields Therapy for Enhancing Glioblastoma Outcomes"

Letter to the Editor: "Imperative for Increased Research into Tumor Treating Fields Therapy for Enhancing Glioblastoma Outcomes"

Abstract 7591: Tumor Treating Fields (TTFields) show efficacy in Triple-Negative breast cancer (TNBC) cells alone and in combination with PARP inhibitor Talazoparib

Abstract Breast cancer is the most common cancer in women worldwide, and the fifth leading cause of cancer-related deaths globally. Triple-negative breast cancer (TNBC), the most aggressive form of breast cancer, is usually treated with surgery, chemotherapy, and radiation. Tumor Treating Fields therapy are FDA-approved for the treatment of glioblastoma (GBM) and malignant pleural mesothelioma (MPM).TT Fields use alternating electric fields to inhibit tumor growth through mitotic disruption, cellular damage, integrated stress response activation, and immune mechanisms and inhibit cell proliferation, induce cell death, and cause cell cycle arrest.TT Fields can induce BRCAness and when combined with PARP inhibition, this combination may result in synthetic lethality. We explored the effect of TTFields on two TNBC cell lines MDA-MB436 (BRCA1-mutant, p53-null) and MDA-MB468 (BRCA1 wild-type, p53-mutant) treated with TTFields (150 kHz) for 24 hours. Western blot analysis showed elevation of p21 independent of p53 mutational status. We examined the combination of PARP inhibitor (Talazoparib) with TTFields in MDA-MB468 cells to determine the effect of the combination in BRCA wild-type cancer cells. Western blot analysis showed p21 upregulation after 24 hours in combination without an increase in p53. p21 acts as a G1-checkpoint protein and loss of p21 expression has been observed in a high percentage of human breast cancer cells. Our results suggest a rational and potentially effective therapy that could be further developed and used for the treatment of breast cancer. Our ongoing studies are exploring potential mechanisms of synergy between PARP inhibitor Talazoparib and TTFields using various TNBC models, and the effect of the combination on cell cycle arrest in cell culture and in vivo. Citation Format: Maryam Ghandali, Praveen Srinivasan, Yutong Xia, Eric T. Wong, Robert W. Sobol, Lanlan zhou, Benedito A. Carneiro, Stephanie L. Graff, Wafik S. El-Deiry. Tumor Treating Fields (TTFields) show efficacy in Triple-Negative breast cancer (TNBC) cells alone and in combination with PARP inhibitor Talazoparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7591.

Bevacizumab and gamma knife radiosurgery for first-recurrence glioblastoma

IntroductionGlioblastoma (GBM) is the most common central nervous system malignancy in adults. Despite decades of developments in surgical management, radiation treatment, chemotherapy, and tumor treating field therapy, GBM remains an ultimately fatal disease. There is currently no definitive standard of care for patients with recurrent glioblastoma (rGBM) following failure of initial management.ObjectiveIn this retrospective cohort study, we set out to examine the relative effects of bevacizumab and Gamma Knife radiosurgery on progression-free survival (PFS) and overall survival (OS) in patients with GBM at first-recurrence.MethodsWe conducted a retrospective review of all patients with rGBM who underwent treatment with bevacizumab and/or Gamma Knife radiosurgery at Roswell Park Comprehensive Cancer Center between 2012 and 2022. Mean PFS and OS were determined for each of our three treatment groups: Bevacizumab Only, Bevacizumab Plus Gamma Knife, and Gamma Knife Only.ResultsPatients in the combined treatment group demonstrated longer post-recurrence median PFS (7.7 months) and median OS (11.5 months) compared to glioblastoma patients previously reported in the literature, and showed improvements in total PFS (p=0.015), total OS (p=0.0050), post-recurrence PFS (p=0.018), and post-recurrence OS (p=0.0082) compared to patients who received either bevacizumab or Gamma Knife as monotherapy.ConclusionThis study demonstrates that the combined use of bevacizumab with concurrent stereotactic radiosurgery can have improve survival in patients with rGBM.

EE363 Cost-Effectiveness Analysis of Adding Tumor Treating Fields Therapy to Temozolomide Versus Temozolomide Only in Patients with Glioblastoma in France

EE363 Cost-Effectiveness Analysis of Adding Tumor Treating Fields Therapy to Temozolomide Versus Temozolomide Only in Patients with Glioblastoma in France

531P Tumor treating fields therapy for glioblastoma: Identifying needs and satisfaction of new and long-term users

531P Tumor treating fields therapy for glioblastoma: Identifying needs and satisfaction of new and long-term users

Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study

Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell survival, leading to immunogenic cell death and enhanced antitumour immune response. In preclinical models of non-small-cell lung cancer, TTFields amplified the effects of chemotherapy and immune checkpoint inhibitors. We report primary results from a pivotal study of TTFields therapy in metastatic non-small-cell lung cancer. This randomised, open-label, pivotal phase 3 study recruited patients at 130 sites in 19 countries. Participants were aged 22 years or older with metastatic non-small-cell lung cancer progressing on or after platinum-based therapy, with squamous or non-squamous histology and ECOG performance status of 2 or less. Previous platinum-based therapy was required, but no restriction was placed on the number or type of previous lines of systemic therapy. Participants were randomly assigned (1:1) to TTFields therapy and standard systemic therapy (investigator's choice of immune checkpoint inhibitor [nivolumab, pembrolizumab, or atezolizumab] or docetaxel) or standard therapy alone. Randomisation was performed centrally using variable blocked randomisation and an interactive voice-web response system, and was stratified by tumour histology, treatment, and region. Systemic therapies were dosed according to local practice guidelines. TTFields therapy (150 kHz) was delivered continuously to the thoracic region with the recommendation to achieve an average of at least 18 h/day device usage. The primary endpoint was overall survival in the intention-to-treat population. The safety population included all patients who received any study therapy and were analysed according to the actual treatment received. The study is registered with ClinicalTrials.gov, NCT02973789. Between Feb 13, 2017, and Nov 19, 2021, 276 patients were enrolled and randomly assigned to receive TTFields therapy with standard therapy (n=137) or standard therapy alone (n=139). The median age was 64 years (IQR 59-70), 178 (64%) were male and 98 (36%) were female, 156 (57%) had non-squamous non-small-cell lung cancer, and 87 (32%) had received a previous immune checkpoint inhibitor. Median follow-up was 10·6 months (IQR 6·1-33·7) for patients receiving TTFields therapy with standard therapy, and 9·5 months (0·1-32·1) for patients receiving standard therapy. Overall survival was significantly longer with TTFields therapy and standard therapy than with standard therapy alone (median 13·2 months [95% CI 10·3-15·5] vs 9·9 months [8·1-11·5]; hazard ratio [HR] 0·74 [95% CI 0·56-0·98]; p=0·035). In the safety population (n=267), serious adverse events of any cause were reported in 70 (53%) of 133 patients receiving TTFields therapy plus standard therapy and 51 (38%) of 134 patients receiving standard therapy alone. The most frequent grade 3-4 adverse events were leukopenia (37 [14%] of 267), pneumonia (28 [10%]), and anaemia (21 [8%]). TTFields therapy-related adverse events were reported in 95 (71%) of 133 patients; these were mostly (81 [85%]) grade 1-2 skin and subcutaneous tissue disorders. There were three deaths related to standard therapy (two due to infections and one due to pulmonary haemorrhage) and no deaths related to TTFields therapy. TTFields therapy added to standard therapy significantly improved overall survival compared with standard therapy alone in metastatic non-small-cell lung cancer after progression on platinum-based therapy without exacerbating systemic toxicities. These data suggest that TTFields therapy is efficacious in metastatic non-small-cell lung cancer and should be considered as a treatment option to manage the disease in this setting. Novocure.

Tumor Treating Fields therapy could potentiate immunotherapy in non-small-cell lung cancer

Tumor Treating Fields therapy could potentiate immunotherapy in non-small-cell lung cancer

Optimization of tumor-treating field therapy for triple-negative breast cancer cells in vitro via frequency modulation

PurposeCurrently, tumor-treating field (TTField) therapy utilizes a single “optimal” frequency of electric fields to achieve maximal cell death in a targeted population of cells. However, because of differences in cell size, shape, and ploidy during mitosis, optimal electric field characteristics for universal maximal cell death may not exist. This study investigated the anti-mitotic effects of modulating electric field frequency as opposed to utilizing uniform electric fields.MethodsWe developed and validated a custom device that delivers a wide variety of electric field and treatment parameters including frequency modulation. We investigated the efficacy of frequency modulating tumor-treating fields on triple-negative breast cancer cells compared to human breast epithelial cells.ResultsWe show that frequency-modulated (FM) TTFields are as selective at treating triple-negative breast cancer (TNBC) as uniform TTFields while having a greater efficacy for combating TNBC cell growth. TTField treatment at a mean frequency of 150 kHz with a frequency range of ± 10 kHz induced apoptosis in a greater number of TNBC cells after 24 h as compared to unmodulated treatment which led to further decreased cell viability after 48 h. Furthermore, all TNBC cells died after 72 h of FM treatment while cells that received unmodulated treatment were able to recover to cell number equivalent to the control.ConclusionTTFields were highly efficacious against TNBC growth, FM TTFields showed minimal effects on epithelial cells similar to unmodulated treatment.

Efficacy and selectivity of tumor-treating field therapy for triple-negative breast cancer cells via in-house delivery device

PurposeTriple-negative breast cancer continues to be one of the leading causes of death in women, making up 7% of all cancer deaths. Tumor-treating electric fields are low-energy, low-frequency oscillating electric fields that induce an anti-proliferative effect on mitotic cells in glioblastoma multiforme, non-small cell lung cancer, and ovarian cancer. Little is known about effects of tumor-treating fields on triple-negative breast cancer and known research for tumor-treating fields only utilizes low (< 3 V/cm) electric field intensities.MethodsWe have developed an in-house field delivery device capable of high levels of customization to explore a much wider variety of electric field and treatment parameters. Furthermore, we investigated the selectivity of tumor-treating field treatment between triple-negative breast cancer and human breast epithelial cells.ResultsTumor-treating fields show greatest efficacy against triple-negative breast cancer cell lines between 1 and 3 V/cm electric field intensities while having little effect on epithelial cells.ConclusionThese results provide a clear therapeutic window for tumor-treating field delivery to triple-negative breast cancer.

Effectiveness and safety of tumor-treating fields therapy for glioblastoma: A single-center study in a Chinese cohort.

Tumor-treating fields (TTFields) are a new therapeutic modality for patients with glioblastoma (GBM). However, studies on survival outcomes of TTFields are rarely reported in China. This study aimed to examine the clinical efficacy and safety of TTFields therapy for GBM in China. A total of 93 patients with newly diagnosed GBM (ndGBM) and recurrent GBM (rGBM) were included in our study retrospectively. They were divided into two groups based on whether they used TTFields. Progression-free survival (PFS), overall survival (OS), and toxicities were assessed. Among the patients with ndGBM, there were 13 cases with TTFields and 39 cases with no TTFields. The median PFS was 15.3 [95% confidence interval (CI): 6.5-24.1] months and 10.6 (95% CI: 5.4-15.8) months in the two groups, respectively, with P = 0.041. The median OS was 24.8 (95% CI: 6.8-42.8) months and 18.6 (95% CI: 11.4-25.8) months, respectively, with P = 0.368. Patients with subtotal resection (STR) who used TTFields had a better PFS than those who did not (P = 0.003). Among the patients with rGBM, there were 13 cases with TTFields and 28 cases with no TTFields. The median PFS in the two groups was 8.4 (95% CI: 1.7-15.2) months and 8.0 (95% CI: 5.8-10.2) months in the two groups, respectively, with P = 0.265. The median OS was 10.6 (95% CI: 4.8-16.4) months and 13.3 (95% CI: 11.0-15.6) months, respectively, with P = 0.655. A total of 21 patients (21/26, 80.8%) with TTFields developed dermatological adverse events (dAEs). All the dAEs could be resolved or controlled. TTFields therapy is a safe and effective treatment for ndGBM, especially in patients with STR. However, it may not improve survival in patients with rGBM.

A comment to improve tumor-treating fields therapy

&lt;abstract&gt; &lt;p&gt;Recent investigations have shown that special frequencies and intensities of electromagnetic waves could control the differentiations of some types of cells. Using this fact, tumor-treating fields (TTFields) therapy has been proposed as a technique which uses alternating electric fields of intermediate frequency (~100–500 kHz) and low intensity (1–3 V/cm) to disrupt the cell divisions of tumors. However, this technique may have harmful effects on ionic liquids around normal cells. For example, electrodes could induce an extra electrical current within blood vessels. To observe these effects, we connected electrodes to a slide that includes water and some extra ions and put them under a 1000× microscope. We found that some ions, microbes and cells move toward negative electrons and some go away. These attractions of cells by electrodes could cause the destruction of the brain. We also found some electrical currents within the liquid emerge which absorb or repel water molecules and induce some bubbles. If these types of bubbles arise within the blood vessels, they can exert a force on the membranes of normal cells and destroy them. To avoid these problems, we suggest that electrodes should be replaced by some electromagnetic sender/receiver which emits some special frequencies. These frequencies could be absorbed only by blood vessels around the tumors because these vessels may be created only to provide the needed food for tumor cells and thus have a different potential and electrical current as compared to vessels around normal cells. Thus, these tumor vessels could act as the antenna for TTFields.&lt;/p&gt; &lt;/abstract&gt;

Glioma stem cell signature predicts the prognosis and the response to tumor treating fields treatment.

Glioma stem cells (GSCs) play an important role in glioma recurrence and chemo-radiotherapy (CRT) resistance. Currently, there is a lack of efficient treatment approaches targeting GSCs. This study aimed to explore the potential personalized treatment of patients with GSC-enriched gliomas. Single-cell RNA sequencing (scRNA-seq) was used to identify the GSC-related genes. Then, machine learning methods were applied for clustering and validation. The least absolute shrinkage and selection operator (LASSO) and COX regression were used to construct the risk scores. Survival analysis was performed. Additionally, the incidence of chemo-radiotherapy resistance, immunotherapy status, and tumor treating field (TTF) therapy response were evaluated in high- and low-risk scores groups. Two GSC clusters exhibited significantly different stemness indices, immune microenvironments, and genomic alterations. Based on GSC clusters, 11-gene GSC risk scores were constructed, which exhibited a high predictive value for prognosis. In terms of therapy, patients with high GSC risk scores had a higher risk of resistance to chemotherapy. TTF therapy can comprehensively inhibit the malignant biological characteristics of the high GSC-risk-score gliomas. Our study constructed a GSC signature consisting of 11 GSC-specific genes and identified its prognostic value in gliomas. TTF is a promising therapeutic approach for patients with GSC-enriched glioma.

A comment to improve tumor treating fields therapy

A comment to improve tumor treating fields therapy

Feasibility of a method for optimizing the electrode array structure in tumor-treating fields therapy

Feasibility of a method for optimizing the electrode array structure in tumor-treating fields therapy

Technical note: Evaluation of methods for reducing edge current density under electrode arrays for tumor-treating fields therapy.

Tumor-treating fields (TTFields) therapy is increasingly utilized clinically because of its demonstrated efficacy in cancer treatment. However, the risk of skin burns must still be reduced to improve patient safety and posttreatment quality of life. The purpose of this study was to evaluate the methods of constructing electrode arrays that reduce current density exceeding threshold values, which can cause skin burns during TTFields therapy. Electrode and body models were generated using COMSOL software. The body model had the dielectric properties of the scalp. The average current density beneath the central region of the electrode was maintained at ∼31mA/cm2 RMS. The deviations in current density at the edges of the electrode were reduced by three methods: adjustment of the ceramic thickness ratio of the center to the edge from 1/5 to 4/5, adjustment of the radius of the metal plate from 5.0 to 8.0mm, and insertion of an insulator of width 0.5 to 2mm at the edge. While using a single circular electrode, adjustment of the ceramic thickness ratio, adjustment of the metal plate radius, and insertion of an insulator near the edge reduced the deviations of current density by 14.6%, 67.7%, and 75.3%, respectively. Similarly, while using circular electrode arrays, inserting an insulator at the edge of each electrode reduced the deviations of current density significantly, from 8.62 to 2.40mA/cm2 . Insertion of an insulator at the edge of each electrode was found to be the most effective method of attaining uniform current density distribution beneath the electrode, thereby lowering the risk of adverse effects of TTFields therapy.

Management of dermatologic adverse events associated with tumor treating fields in patients with glioblastoma multiforme: A 27-case series

ObjectiveThis study summarized the clinical management of 27 patients with glioblastoma multiforme who tumor treating fields therapy for the healthcare providers. MethodsGlioblastoma multiforme patients who experienced dermatologic adverse events after tumor treating fields therapy from April 2019 to May 2021 were included. The clinical management involved educating patients and their caregivers on the prevention of dermatologic adverse events, scalp assessment and preparation, and removal and replacement of the transducer array. Informed consent for participating in the study including the taking of pictures was obtained from all patients. ResultsThe dermatologic adverse events were successfully managed in all 27 patients, with no severe dermatologic adverse events were reported. ConclusionsData on tumor treating fields-related dermatologic adverse events is rarely reported, and published reports of management of scalp dermatologic adverse events are lacking. This case series summarizes a clinically individualized management for tumor treating fields-related dermatologic adverse events.

Lucanthone Targets Lysosomes to Perturb Glioma Proliferation, Chemoresistance and Stemness, and Slows Tumor Growth In Vivo.

Glioblastoma is the most common and aggressive primary brain tumor in adults. Median survival time remains at 16-20 months despite multimodal treatment with surgical resection, radiation, temozolomide and tumor-treating fields therapy. After genotoxic stress glioma cells initiate cytoprotective autophagy, which contributes to treatment resistance, limiting the efficacy of these therapies and providing an avenue for glioma recurrence. Antagonism of autophagy steps has recently gained attention as it may enhance the efficacy of classical chemotherapies and newer immune-stimulating therapies. The modulation of autophagy in the clinic is limited by the low potency of common autophagy inhibitors and the inability of newer ones to cross the blood-brain barrier. Herein, we leverage lucanthone, an anti-schistosomal agent which crosses the blood-brain barrier and was recently reported to act as an autophagy inhibitor in breast cancer cells. Our studies show that lucanthone was toxic to glioma cells by inhibiting autophagy. It enhanced anti-glioma temozolomide (TMZ) efficacy at sub-cytotoxic concentrations, and suppressed the growth of stem-like glioma cells and temozolomide-resistant glioma stem cells. In vivo lucanthone slowed tumor growth: reduced numbers of Olig2+ glioma cells, normalized tumor vasculature, and reduced tumor hypoxia. We propose that lucanthone may serve to perturb a mechanism of temozolomide resistance and allow for successful treatment of TMZ-resistant glioblastoma.

Efficacy and safety of tumor-treating fields in recurrent glioblastoma: a systematic review and meta-analysis.

Tumor-treating fields (TTF) is a novel cancer treatment that uses alternating electric fields to interfere with tumor cell mitosis. It has been approved by the U.S. food and drug administration for the treatment of recurrent glioblastoma (rGBM). We designed this meta-analysis to evaluate the efficacy and safety of TTF in the treatment of rGBM. The study was based on the PRISMA guideline. Systematic retrieval was performed in PubMed, Cochrane Library, and Embase databases. The outcomes were overall survival (OS) hazard ratio (HR), 1-year survival rate, and cutaneous toxicity. These studies included a total of 1048 rGBM patients who received TTF treatment. The overall survival time between the TTF group and the control group was HR 0.75 ([95%CI 0.63 to 0.89]; P = 0.001). Pooled 1-year overall survival rate and incidence of cutaneous toxicity were 0.47 and 0.48, respectively. Data were insufficient to evaluate the effect of MGMT methylation status and tumor recurrence times on heterogeneity. TTF therapy is effective for recurrent glioblastoma. However, most relevant trials should assess rGBM patient baseline characteristics such as age, KPS, MGMT methylation status, and number of tumor recurrence,. In addition, the risk of rashes caused by long-term wearing of devices should also be considered.

Tumor treating fields therapy is feasible and safe in a 3-year-old patient with diffuse midline glioma H3K27M — a case report

Since high grade gliomas are aggressive brain tumors, intensive search for new treatment options is ongoing. For adult patients with newly diagnosed (ndGBM) and recurrent glioblastoma (rGBM), low intensity intermediate frequency alternating electric fields, known as tumor treating fields (TTFields) have been established as a new treatment modality. Tumor treating fields significantly increase survival rates in combination with adjuvant temozolomide (TMZ) in adult and GBM patients. Here, we report about feasibility and safety of treatment on a pediatric patient with diffuse midline glioma who is receiving TTFields therapy in combination with temozolomide.

A novel microscale platform for leukemia tumor treating field therapy and electrochemical screening

Currently, chemotherapy methods are among the most commonly used strategies for all cancer treatments, including leukemia. Despite the marked successes of such therapies, their inevitable side-effects and dose-limiting complications hinder reaching the maximum efficacy. Recently, Tumor Treating Fields (TTFields) that exploits low intensity and intermediate frequency electric fields has shown great promise as a noninvasive cancer therapy. Combining TTFields and conventional chemotherapies allows treatment with lower drug doses, resulting in significant clinical outcomes and fewer side effects. Although such combinational therapies have been used to treat a wide range of cancer types, their potential applications on leukemia have yet to be explored. This study investigates the effects of TTFields on the leukemia cells in combination with imatinib using a novel microelectrode array platform enabling the on-chip application of TTFields. Microfabrication allows applying TTFields by conventional signal generators with a maximum 20 V peak-to-peak external voltage eliminating commonly used high voltage amplifiers. We evaluated the effectiveness of our method with several biological assays, including flow cytometry, Annexin-V staining, and MTT. Our results indicate that combining TTFields and imatinib can halve the required drug dose (1 μM to 0.5 μM) to reach the apoptotic rate (68.55%±2.4%) obtained by imatinib alone. By comparing the cells numbers, after 72 h, the K562 cells number in our combinational treatment were 7% lower than the initial values seeded, suggesting a considerable net reduction in the tumor cell. Furthermore, to explore the underlying mechanism, an electrochemical approach is employed to measure the secreting contents of the leukemia cells after treatment. We concluded that the enhancement in treatment efficacy could be attributed to the induction of intracellular reactive oxygen species by TTFields, resulting in increased cell apoptosis. Our method provides an in vitro basis to assess the application of TTFields in combination with chemotherapy for leukemia cells.