A novel combination therapy using electric fields alongside immunotherapy has shown promising results for treating glioblastoma, the most aggressive form of brain cancer. Researchers at Keck Medicine of the University of Southern California found that combining Tumor Treating Fields (TTFields) with immunotherapy and chemotherapy increased overall survival by 70% compared to historical controls using TTFields and chemotherapy alone.
The findings, published in Med, emerge from the 2-THE-TOP Phase 2 clinical trial, which enrolled 31 newly diagnosed glioblastoma patients who had completed chemoradiation therapy. Of these, 26 patients received the triple combination treatment.
Overcoming the Blood-Brain Barrier Challenge
Glioblastoma presents unique treatment challenges due to the blood-brain barrier, which restricts immune cell access to the brain and limits immunotherapy effectiveness. The average survival for glioblastoma patients is just eight months after diagnosis, according to the National Brain Tumor Society.
"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 and corresponding author of the study. "Our findings suggest that TTFields may be the key to unlocking the value of immunotherapy in treating glioblastoma."
How TTFields Enhance Immune Response
TTFields interfere with cancer cell division by altering internal structures through rapidly changing electric fields delivered via scalp-mounted electrodes. These fields are tuned to specific frequencies targeting the tumor's location, with patients wearing the electrodes approximately 18 hours daily.
The study revealed that TTFields promoted stronger immune responses by increasing T cell presence within and around tumors. When used prior to immunotherapy with pembrolizumab, an immune checkpoint inhibitor, TTFields enhanced the immune system's ability to sustain and replace T cells with more potent cancer-fighting cells.
This approach, known as in situ immunization, bypasses the blood-brain barrier restrictions by initiating immune responses directly inside the tumor. "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)," Tran explained.
Unexpected Findings in Inoperable Tumors
The trial included seven patients with large, inoperable tumors that had not been surgically removed—a group typically facing limited treatment options and worse prognosis. Surprisingly, these patients demonstrated particularly strong responses to the combination therapy.
Patients with large, inoperable tumors lived approximately 13 months longer and showed much stronger immune activation compared to patients who underwent surgical tumor removal. This suggests that larger tumors may provide more targets for the therapy to work against when kick-starting the body's immune response.
"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.
Treatment Protocol and Results
In the trial, patients received six to 12 monthly chemotherapy treatments (temozolomide) alongside TTFields for up to 24 months, with treatment duration determined by individual patient response. Pembrolizumab immunotherapy was administered every three weeks, starting with the second chemotherapy cycle, for up to 24 months.
The combination therapy resulted in patients living approximately 10 months longer than those who had previously used TTFields with chemotherapy alone. The 70% improvement in overall survival represents a significant advancement for a cancer type with historically poor outcomes.
Phase 3 Validation Underway
A Phase 3 clinical trial is currently validating these findings across more than 740 participants at 28 sites in the United States, Europe, and Israel. The trial includes patients with varying degrees of tumor resection and aims to determine whether surgical tumor removal affects immunologic and survival outcomes of the combination treatment.
Tran, who chairs the steering committee for this Phase 3 trial, expects the study to continue through April 2029. The trial will assess patients with gross total resection, partial resection, or biopsy-only tumors to better understand how surgical intervention influences immune response to the combination therapy.
