Electric Fields May Help the Immune System Fight Brain Cancer

A study led by researchers at Keck Medicine of the University of Southern California suggests that using an alternating electric field device on the scalp, combined with immunotherapy and chemotherapy, may extend survival for people with glioblastoma.

The findings were drawn from a Phase 2 trial of a multimodal approach that integrated Tumor Treating Fields (TTFields), a non-invasive therapy that targets cancer cells with low-intensity, alternating electric fields. The research was published in Med.

Disrupting tumor growth and drawing immune cells

Glioblastoma is one of the most aggressive forms of brain cancer, with an average survival of just eight months after diagnosis, according to the National Brain Tumor Society. 

TTFields interfere with the division of cancer cells by altering internal structures through rapidly changing electric fields. Delivered through scalp-mounted electrodes, these fields are tuned to a specific frequency that targets the tumor’s location.

Although TTFields and chemotherapy are currently used in treatment, outcomes remain poor. However, in this study, adding immunotherapy to TTFields and chemotherapy was associated with a 70% increase in overall survival. 

Researchers observed that TTFields promoted a stronger immune response by increasing the presence of T cells – white blood cells that recognize and destroy cancer cells – within and around the tumor. When used prior to immunotherapy with pembrolizumab, an immune checkpoint inhibitor, TTFields appeared to enhance the ability of the immune system to sustain and replace T cells with more potent cancer-fighting cells.

“By using TTFields with immunotherapy, we prime the body to mount an attack on the cancer, which enables the immunotherapy to have a meaningful effect in ways that it could not before,” said David Tran, MD, PhD, chief of neuro-oncology with Keck Medicine, co-director of the USC Brain Tumor Center and corresponding author of the study. “Our findings suggest that TTFields may be the key to unlocking the value of immunotherapy in treating glioblastoma.”

Larger tumors showed a stronger response

The study analyzed data from 2-THE-TOP, a Phase 2 clinical trial which enrolled 31 newly diagnosed glioblastoma patients who had completed chemoradiation therapy. Of these, 26 received TTFields alongside both chemotherapy (temozolomide) and immunotherapy. Seven participants had large, inoperable tumors that had not been surgically removed, a group that typically has limited treatment options and a worse prognosis.

Patients underwent up to 24 months of TTFields and chemotherapy, with pembrolizumab introduced during the second chemotherapy cycle and continued every three weeks. The combination of the three therapies was associated with a 70% improvement in overall survival compared to historical controls using TTFields and chemotherapy alone. 

Notably, those with large, inoperable tumors lived approximately 13 months longer and showed much stronger immune activation compared to patients who underwent surgical removal of their tumors. This suggests that, when it comes to kick-starting the body’s immune response against the cancer, having a larger tumor may provide more targets for the therapy to work against.  

“Further studies are needed to determine the optimal role of surgery in this setting, but these findings may offer hope, particularly for glioblastoma patients who do not have surgery as an option,” said Tran, who is also a member of the USC Norris Comprehensive Cancer Center.

Overcoming the blood-brain barrier

The immune suppression observed in glioblastoma is partly due to the blood-brain barrier, which restricts immune cell access to the brain. This barrier also limits the effectiveness of immunotherapies. The strategy of initiating an immune response inside the tumor itself, known as in situ immunization, was intended to bypass these restrictions.

By stimulating local immune activity through TTFields, the researchers aimed to create conditions under which immune checkpoint inhibitors like pembrolizumab could be more effective. The findings support this concept, showing that TTFields can recondition the tumor environment and potentially allow other therapies to work more efficiently.

“Think of it like a team sport — immunotherapy sends players in to attack the tumor (the offense), while TTFields weaken the tumor’s ability to fight back (the defense). And just like in team sports, the best defense is a good offense,” said Tran.

Ongoing clinical investigation

A Phase 3 clinical trial is now underway to validate these findings across more than 740 participants. The trial includes patients with varying degrees of tumor resection and is active at over two dozen sites across the United States, Europe and Israel. It aims to determine whether surgical removal of tumors affects the immunologic and survival outcomes of this combination treatment.

The trial is being chaired by one of the study’s lead researchers and is expected to continue through April 2029.

Reference: Chen D, Le SB, Ghiaseddin AP, et al. Efficacy and safety of adjuvant TTFields plus pembrolizumab and temozolomide in newly diagnosed glioblastoma: A phase 2 study. Med. 2025:100708. doi: 10.1016/j.medj.2025.100708

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