Beyond Glioblastoma: TTFields Ongoing Trials and Potential Synergies in Cancer Therapies

 

Tumor Treating Fields 

Tumor Treating Fields (TTFields) therapy is an emerging and innovative cancer treatment that uses alternating electric fields to disrupt cancer cell division. TTFields therapy delivers low intensity, intermediate frequency electric fields through insulated electrode arrays placed on the skin of cancer patients. These electric fields disrupt mitosis in rapidly dividing cancer cells, inhibiting their ability to clump together and form tumors. Over the past decade, TTFields therapy has emerged as a promising treatment option for various types of cancer. In this article, we provide an overview of TTFields therapy, its mechanism of action and current applications.

How Do TTFields Work?

TTFields therapy works through a distinct mechanism compared to chemotherapy or radiation therapy. While chemotherapy damages DNA and radiation directly destroys cancer cells, TTFields harness the natural process of cells dividing through mitosis. During mitosis, cancer cells develop an electric forceseparation of charged particles called dipoles within the cell. TTFields work by generating low intensity intermediate frequency electric fields through insulated electrode arrays placed on the patient's skin. These externally generated alternating electric fields interfere with the natural separation of dipoles in cancer cells, disrupting mitosis and blocking the cells from completing cell division. This inhibition of mitosis prevents cancer cells from rapidly multiplying and forming new tumors. However, TTFields have minimal effect on normal cells as they divide less rapidly.

Mechanism of Action

Researchers have gained insights into exactly how TTFields generate their anti-tumor effects. During metaphase in cell division, mitotic spindles comprised of microtubule proteins organize and line up chromosomes. Tumor Treating Fields  disrupt the mitotic spindles through dielectric polarization and dielectrophoretic forces. This prevents the proper segregation of chromosomes between dividing cancer cells. As a result, mitosis cannot be completed and the cells are blocked at the G2/M phase border. Over successive cell cycles, TTFields accumulation leads to irreversible mitotic arrest and programmed cell death called apoptosis. Scientists have observed characteristic defects in chromosome alignment and segregation when exposing cancer cells to TTFields in vitro and in vivo. This selective disruption of rapidly dividing cancer cells is the core mechanism of TTFields therapy.

Approved Cancer Applications

Based on positive clinical trial results, the US Food and Drug Administration has approved TTFields therapy for two advanced cancer types - glioblastoma and malignant pleural mesothelioma.

Glioblastoma is an aggressive type of brain cancer with poor survival rates. In a pivotal phase 3 clinical trial published in 2015, TTFields were shown to significantly improve both progression-free and overall survival when used together with chemotherapy for recurrent glioblastoma compared to chemotherapy alone. Based on this and additional supportive data, TTFields was approved as a treatment option for newly diagnosed and recurrent glioblastoma.

For malignant pleural mesothelioma, a rare cancer caused by asbestos exposure, TTFields provide another treatment option beyond chemotherapy. In a phase 3 trial published in 2019, TTFields added to pemetrexed and platinum-based chemotherapy demonstrated a clinically meaningful improvement in progression-free survival compared to chemotherapy alone. This led to FDA approval of TTFields for malignant pleural mesothelioma.

Ongoing Research and New Indications

Encouraged by the success in glioblastoma and mesothelioma, ongoing research aims to expand the applications of TTFields therapy to other cancers. Several phase 2 studies are evaluating TTFields in combination with chemotherapy or immunotherapies for solid tumors like non-small cell lung cancer, pancreatic cancer, ovarian cancer and other types. Early results from some of these trials have been promising, with manageable side effects reported.

Larger phase 3 trials are currently underway to confirm the activity of TTFields in additional cancer types like pancreatic cancer, non-small cell lung cancer and brain metastases. If positive results are obtained, TTFields may gain additional FDA approvals in the coming years for these cancers. Scientists are also gaining deeper insights into TTFields dosimetry, tumor specific field parameters and biomarkers of response through translational studies. This research helps optimize TTFields therapy and tailor it more effectively for individual patients.

Safety Profile and Patient Experience

An advantage of TTFields is that it lacks the harsh side effects of chemotherapy and targeted cancer drugs. The most common adverse reactions are mild skin irritation at the electrode placement sites which can be managed. More seriously, rare cases of seizures have occurred in a small percentage (<3%) of glioblastoma patients receiving TTFields and anti-seizure medications are used prophylactically. So far, no long term safety issues have emerged with this novel cancer treatment modality.

Importantly, TTFields therapy allows patients to maintain an active lifestyle with portable, wearable electric field generators connected to insulated electrode arrays placed on the shaved scalp or chest wall. Controlled clinical trials point to an acceptable quality of life for patients undergoing TTFields maintenance therapy. Overall, TTFields provide a well-tolerated treatment alternative to chemotherapy for approved cancer types.

In summary, Tumor Treating Fields is an innovative cancer treatment modality that harnesses low intensity intermediate frequency electric fields to selectively disrupt mitosis in rapidly dividing cancer cells. Clinical trials have demonstrated the anti-tumor activity of TTFields in glioblastoma and mesothelioma, leading to FDA approval for these indications. Ongoing research aims to elucidate the molecular mechanisms of action further as well as expand TTFields therapy to additional cancers either alone or in combination with standard therapies. With an excellent safety profile and quality of life for patients, TTFields therapy holds promise as part of the evolving landscape of cancer care.

 

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