TTFields alone and in combination with chemotherapeutic agents effectively reduce the viability of MDR cell sub-lines that over-express ABC transporters

<p>Abstract</p> <p>Background</p> <p>Exposure of cancer cells to chemotherapeutic agents may result in reduced sensitivity to structurally unrelated agents, a phenomenon known as multidrug resistance, MDR. The purpose of this study is to investigate cell growth inhibition of wild type and the corresponding MDR cells by Tumor Treating Fields - TTFields, a new cancer treatment modality that is free of systemic toxicity. The TTFields were applied alone and in combination with paclitaxel and doxorubicin.</p> <p>Methods</p> <p>Three pairs of wild type/MDR cell lines, having resistivity resulting from over-expression of ABC transporters, were studied: a clonal derivative (C11) of parental Chinese hamster ovary AA8 cells and their emetine-resistant sub-line Emt^R1; human breast cancer cells MCF-7 and their mitoxantrone-resistant sub lines MCF-7/Mx and human breast cancer cells MDA-MB-231 and their doxorubicin resistant MDA-MB-231/Dox cells. TTFields were applied for 72 hours with and without the chemotherapeutic agents. The numbers of viable cells in the treated cultures and the untreated control groups were determined using the XTT assay. Student t-test was applied to asses the significance of the differences between results obtained for each of the three cell pairs.</p> <p>Results</p> <p>TTFields caused a similar reduction in the number of viable cells of wild type and MDR cells. Treatments by TTFields/drug combinations resulted in a similar increased reduction in cell survival of wild type and MDR cells. TTFields had no effect on intracellular doxorubicin accumulation in both wild type and MDR cells.</p> <p>Conclusions</p> <p>The results indicate that TTFields alone and in combination with paclitaxel and doxorubicin effectively reduce the viability of both wild type and MDR cell sub-lines and thus can potentially be used as an effective treatment of drug resistant tumors.</p

Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs

Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors. TTFields were tested for their potential to inhibit metastatic spread of solid tumors to the lungs in two animal models: (1) Mice injected with malignant melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were treated using two-directional TTFields at 100–200 kHz. Animals were either monitored for survival, or sacrificed for pathological and histological analysis of the lungs. The total number of lung surface metastases and the absolute weight of the lungs were both significantly lower in TTFields treated mice then in sham control mice. TTFields treated rabbits survived longer than sham control animals. This extension in survival was found to be due to an inhibition of metastatic spread, seeding or growth in the lungs of TTFields treated rabbits compared to controls. Histologically, extensive peri- and intra-tumoral immune cell infiltration was seen in TTFields treated rabbits only. These results raise the possibility that in addition to their proven inhibitory effect on the growth of solid tumors, TTFields may also have clinical benefit in the prevention of metastatic spread from primary tumors

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma

This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per cycle) was tested in patients with colorectal cancer receiving FOLFOX in a phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial. Outcome measures included changes in 24-week quantitative measures of thermal sensitivity and total neuropathy score. In total, 124 patients were randomized (1:1) to MR309 or placebo. Sixty-three (50.8%) patients withdrew prematurely before completing 12 planned oxaliplatin cycles. Premature withdrawal because of cancer progression was less frequent in the MR309 group (7.4% vs 25.0% with placebo; p = 0.054). MR309 significantly reduced cold pain threshold temperature [mean treatment effect difference (SE) vs placebo: 5.29 (1.60)degrees C; p = 0.001] and suprathreshold cold stimulus-evoked pain intensity [mean treatment effect difference: 1.24 (0.57) points; p = 0.032]. Total neuropathy score, health-related quality-of-life measures, and nerve-conduction parameters changed similarly in both arms, whereas the proportion of patients with severe chronic neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events >= 3) was significantly lower in the MR309 group (3.0% vs 18.2% with placebo; p = 0.046). The total amount of oxaliplatin delivered was greater in the active arm (1618.9 mg vs 1453.8 mg with placebo; p = 0.049). Overall, 19.0% of patients experienced at least 1 treatment-related adverse event (25.8% and 11.9% with MR309 and placebo, respectively). Intermittent treatment with MR309 was associated with reduced acute oxaipn and higher oxaliplatin exposure, and showed a potential neuroprotective role for chronic cumulative oxaipn. Furthermore, MR309 showed an acceptable safety profile

Tumor Treating Fields for Glioblastoma Treatment: Patient Satisfaction and Compliance With the Second-Generation Optune System

Background: Tumor treating fields (TTFields) are a non-invasive antimitotic therapy that delivers alternating electric fields via the Optune ® system. The Phase III EF-14 trial in newly diagnosed glioblastoma multiforme (GBM) showed significantly improved progression-free, overall and long-term survival when Optune was used together with maintenance temozolomide (TMZ) compared with TMZ alone. Compliance (average monthly use) was associated with better clinical outcome. The first-generation Optune system weighed approximately 6 pounds (~2.7 kg). The second-generation redesigned Optune system weighs 2.7 pounds (~1.2 kg). We tested and compared GBM patient experience with the second-generation system versus the first-generation system. Methods: Ten newly diagnosed and recurrent GBM patients in Germany (median age: 52.9 years [31-79]) were prospectively monitored over the first month of transitioning from the first-generation to the second-generation Optune system. Questionnaires using a numerical analog scale assessed feedback at baseline (first generation) and after 1 month of second-generation use. Results: After transitioning to the second-generation system, compliance improved by more than 10% in four patients, was maintained in five patients and decreased by more than 10% in one patient. Following transition, eight out of nine patients reported a reduction in the triggering of malfunction alarms. Self-reported patient feedback showed improved handling and portability (weight, mobility) of the second- versus the first-generation Optune system. Conclusions: This patient user survey suggests that patient satisfaction with the second-generation Optune system is improved versus the first-generation system. Improved features of the new system help patients achieve and maintain a higher rate of treatment compliance

Abstract CT420: An open label pilot study of NovoTTF Therapy concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma (NCT01971281)

Abstract Background: NovoTTF Therapy is a non-invasive, anti-mitotic treatment modality, based on low intensity alternating electric fields. Tumor Treating Fields (TTFields) interfere with two steps during mitosis: The formation of the mitotic spindle (metaphase), and the translocation of charged organelles (anaphase). TTFields inhibit proliferation of pancreatic cell lines in vitro, and inhibit pancreatic tumor growth in vivo, alone and in combination with gemcitabine. NovoTTF Therapy applied to the brain in recurrent GBM patients demonstrated an anti-tumoral effect with minimal toxicity and better quality of life, compared to chemotherapy (Stupp et al, 2012). Being a regional treatment, TTFields can potentially inhibit the primary tumor as well as major metastatic sites of pancreatic adenocarcinoma. Objectives: the current trial is designed to study the safety, tolerability and efficacy of NovoTTF therapy applied to the abdomen concomitant to the standard care gemcitabine treatment, in patients suffering from advanced pancreatic adenocarcinoma. Endpoints: severity and frequency of adverse events associated with the experimental treatment (primary), progression free survival (PFS), 6-month PFS rate, overall survival, overall response rate, compliance with NovoTTF Therapy (secondary) Treatments: Gemcitabine 1000 mg/m^2 over 30 minute infusion once weekly for up to 7 weeks, followed by a week rest from treatment. Subsequent cycles will consist of once weekly infusions on days 1, 8, 15 every 28 days. Continuous NovoTTF Therapy at a frequency of 150 kHz will be administered to the abdomen, in order to cover the region of primary tumor and main metastatic sites. The fields will be applied in two perpendicular directions at a maximal intensity of 1414 mA RMS, using highly insulated Transducer Arrays connected to a portable, battery-operated electric field generator. TTFields will be administered for at least 18 hours a day until radiological disease progression. Major eligibility criteria: unresectable, pathologically confirmed, locally advanced/metastatic pancreatic adenocarcinoma, measurable/assessable disease, ECOG score 0-1, no prior chemotherapy or radiation, no implantable electronic medical devices. Citation Format: Uri Weinberg, Eilon D. Kirson, Ori Farber, Moshe Giladi, Yoram Palti. An open label pilot study of NovoTTF Therapy concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma (NCT01971281). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT420. doi:10.1158/1538-7445.AM2014-CT420</jats:p