By Michelle Jaffee
University of Florida neuroscientists have discovered a new potential benefit of a form of electric fields therapy currently in use to treat glioblastoma, the deadliest form of brain cancer in adults.
The preclinical and patient data research, published online Feb. 24 in the Journal of Clinical Investigation, showed that Tumor Treating Fields, or TTFields, appears to offer a potential simultaneous benefit of stimulating the immune system to help protect against tumor recurrence.
TTFields is approved by the Food and Drug Administration to treat glioblastoma and malignant mesothelioma. For glioblastoma, electrodes attached to the head transmit low-intensity electric fields that disrupt cancer cell division. TTFields therapy is intended principally to be used together with chemotherapy treatment.
In the new study, David D. Tran, M.D., Ph.D., chief of the division of neuro-oncology in UF’s Lillian S. Wells Department of Neurosurgery, Dongjiang Chen, M.D., research assistant professor, and colleagues demonstrate a mechanism by which they reported TTFields served as a form of immunotherapy, or a way to harness the power of the body’s own immune system to fight cancer.
The research team used biochemical, molecular and imaging methods coupled with advanced single cell genomics and computational methods to show how the mechanism worked in glioblastoma patient-derived cancer stem cells and mouse models of glioblastoma and in 12 human clinical trial participants treated with TTFields.
“We found something completely unexpected,” Tran said. “The electric fields, when applied at the same frequency and intensity as used in human patients, cause the nuclear envelope of cancer cells to rupture, creating small holes. Through these holes, the nuclear content spills out into the cytoplasm of cancer cells. And that’s where the light bulb went on in our heads, because this is the same phenomenon when human cells are infected with viruses or bacteria that invade cells. The nuclear material that leaks into the cytoplasm stimulates the two major inflammatory pathways known as cGAS/STING and AIM2.”
That, he said, can set up a powerful inflammatory reaction.
“TTFields, in essence, is a vaccinating machine,” Tran said. “It creates a robust inflammatory reaction, causing the tumor cells to burst open, which then also provides the tumor proteins for the immune system to recognize. We show that you can actually use TTFields to vaccinate animals against glioblastoma, and the animals can develop a memory immune reaction to clear the tumor and prevent future recurrence. The same immune activation pathway was later identified in trial participants treated with TTFields.”
The new findings are the latest step in evolving research on TTFields. With the device, Tran said, “previous clinical data show that TTFields improved survival by five months on average for glioblastoma, which is about twice as much as chemotherapy.” Median survival for glioblastoma with TTFields is approximately 21 months, Tran said.
Over the last few years, new research has suggested TTFields appears to induce inflammation, prompting the UF research team to pursue whether it could provide an additional protective effect against new tumor growth and prolong life.
The vaccination effect is delivered externally through the electrodes, thus there is no need to surgically remove the tumor or isolate immune cells or generate complex chemical formulations to create a vaccine, Tran said. “Basically, TTFields-treated glioblastoma cells provide the complete tumor vaccination platform for glioblastoma, and potentially other cancers as well,” he said.
TTFields is in late-stage clinical testing for additional forms of cancer.
The study also identified a gene-based biomarker panel that could be used to predict response to the immunological effects of TTFields in glioblastoma patients that could be useful as researchers continue to study and develop the new application for TTFields, Tran said.
TTFields is being studied in an ongoing phase 2 pilot clinical trial at UF called 2-THE-TOP for patients with newly diagnosed glioblastoma. In the trial, led by Tran, TTFields is combined with Keytruda, an immune checkpoint inhibitor medication and the chemotherapy drug Temodar. Findings for the 26-patient trial are expected later this year. Early trial data was presented at the Society for Neuro-Oncology annual meeting last November, and the abstract is a top 10 abstract winner at the upcoming Quadrennial Meeting of the World Federation of Neuro-Oncology Societies in March.
“Ongoing work is focused on understanding the key immune cells and signals that can be used to identify those patients who would benefit the most from this approach and understand why some patients do not,” Tran said. “This knowledge will help further improve the novel treatment strategy to benefit a much larger percentage of patients. This also has significant implications for TTFields as a potential novel immunotherapy in other cancers.”
David D. Tran has received research grants from Novocure to support parts of this research and also serves on the medical advisory board of Novocure. He and co-author Dongjiang Chen are inventors of two patent applications based on the data.