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Originally published June 3, 2025
Last updated June 3, 2025
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Immunotherapies such as immune checkpoint inhibitors have transformed the immune system’s ability to detect and eliminate cancer cells — particularly in “hot” tumors like lung and kidney cancers. Because these tumors originate in tissues rich in T cells, they often mount strong responses when drugs block the tumor’s mechanisms for evading immune detection. By contrast, “cold” tumors — such as glioblastoma, pancreatic cancer and prostate cancer — remain resistant to immune checkpoint blockade. These “cold” cancers thrive in highly immunosuppressive microenvironments — in glioblastoma’s case, within the brain — effectively preventing an effective anti-tumor immune response.
Could adding alternating electrical field therapy (also known as Tumor Treating Fields, or TTFields) improve immunotherapy’s efficacy for glioblastoma?
A newly published study led by David D. Tran, MD, PhD — chief of neuro-oncology and co-director of the USC Brain Tumor Center, part of Keck Medicine of USC — evaluated a combination of TTFields and the checkpoint inhibitor Keytruda in newly diagnosed glioblastoma patients. Their findings lay the foundation for further testing to establish a new standard of care for glioblastomas, especially for patients with bulky, inoperable tumors who have historically faced limited treatment options.
Tran explains why glioblastomas resist immunotherapies like checkpoint inhibitors. Unlike other cancers that arise elsewhere and later spread to the brain, glioblastomas originate in the brain’s immune-privileged environment. “Immune cells simply don’t traffic into the brain efficiently,” he says. “Because the tumor develops inside this sanctuary, it remains largely shielded from the immune system.”
Glioblastomas also have very few T cells. “For this reason, checkpoint inhibitor drugs alone are often ineffective — there simply aren’t enough immune cells in the tumor for the checkpoint inhibitors to engage,” Tran explains.
Instead, he says, “We first need to generate a strong anti-tumor immune reaction to recruit immune cells to the tumor — and TTFields serve as that catalyst.”
In 2011, the FDA approved TTFields as a treatment for recurrent glioblastomas, and in 2015, it was approved for newly diagnosed glioblastoma following surgery, radiation therapy and chemotherapy.
TTFields is a noninvasive treatment that delivers intermediate frequency alternating electric fields through arrays the patient wears on their head. (The patient’s head is shaved, and the arrays are glued to the scalp.) Built into the arrays are electrode discs in which electrodes are embedded into a mesh material that sits flush on the scalp. The electrode arrays are positioned differently for each patient depending on where their glioblastoma is in the brain. Attached to the arrays is the small, portable, battery-powered device. When turned on, the device sends electric fields through the electrodes.
These fields exert an antimitotic effect on tumor cells by disrupting cell division and inducing apoptosis. TTFields are often administered together with chemotherapy — most commonly temozolomide in glioblastoma — which also targets rapidly dividing cells.
Apoptosis is a “clean” form of cell death. “The tumor cells simply collapse, and immune cells clear them away,” Tran says. “Because cellular contents remain contained, very little spills out, and inflammation is minimal.”
However, in glioblastoma patients treated with TTFields, Tran — who has studied this technology for more than a decade — observed the opposite of the expected “clean” effect. Post-treatment brain MRI revealed pronounced inflammatory changes rather than quiescent tissue. Although these tumors ultimately responded well to therapy, they initially exhibited a robust surge of inflammation.
Tran and his colleagues recognized this surge as pseudoprogression — a phenomenon recently described in immunotherapy and cancer treatment.
“For patients treated with TTFields who ultimately responded well, for the first three to four months their scans often suggested the tumor was worsening rather than improving,” he explains. “We regularly saw imaging that looked like progression, even though patients were doing just fine, experienced minimal symptoms and tolerated the treatment without issue.”
In reality, the tumor hadn’t grown; instead, Tran and colleagues were observing inflammation activated by an immune response — specifically, activation of the type-I interferon pathway via DNA sensor–dependent inflammasomes.
“At first, the alternating electric fields create tiny holes in tumor cells’ nuclear envelope, allowing DNA contained in the nucleus to leak into the cytoplasm,” Tran explains. “When DNA appears where it doesn’t belong, it triggers a potent inflammatory response. This same mechanism typically serves as a natural alarm during viral infections, alerting the immune system to the presence of foreign DNA material.”
Crucially, this inflammation jump-starts a powerful immune reaction. “The tumor behaves as if it were infected with a virus,” Tran explains. “That creates what we call an in situ immunizing effect — essentially a cancer vaccine generated right within the tumor. Suddenly, a mass that was previously invisible to the immune system becomes unmistakable, provoking a robust immune response. In our 2022 study, we showed that TTFields act as an internal ‘vaccine machine,’ teaching the immune system to recognize and eradicate the tumor. In other words, we turned a cold tumor hot.”
Once the immune reaction was generated, adding immunotherapy became the obvious next step. “By first generating tumor-specific immune reactions, we set the stage to pair TTFields with an immune checkpoint inhibitor — and the combination produced a true synergistic effect,” Tran says.
In their new Phase 2 trial in newly diagnosed glioblastoma patients, Tran and co-authors administered TTFields treatment and temozolomide chemotherapy first, then added the immune checkpoint inhibitor drug Keytruda (pembrolizumab, an anti-PD-1 monoclonal antibody).
Thirty-one newly diagnosed glioblastoma patients were enrolled in the study after receiving chemotherapy and radiation therapy. The patients included those who had maximal resection of their glioblastoma as well as biopsy-only patients.
The patients wore the TTFields arrays while receiving one cycle of adjuvant chemotherapy temozolomide. One month later, 200 mg of intravenous Keytruda was added to the regimen, administered every three weeks.
“The reason for this design is that we wanted to have a window of time during which there was no Keytruda given so that we could measure the effects of the TTFields and chemotherapy alone,” Tran explains. “Then after that, we measured the effect of the Keytruda, the TTFields and the chemotherapy together.”
Tumor size was assessed by MRI before, during and after treatment. Concurrently, the researchers performed advanced single-cell genomic analysis on blood samples collected at the same time points as well as tumor samples before treatment and at recurrence to detect emerging anti-tumor activity. Many have questioned whether a blood-based immune readout can reliably reflect what’s happening to the tumor in the brain. Tran responds: “We understand this concern, but TTFields generate a robust, localized inflammatory response in the tumor itself. That signal is strong enough to spill over into the bloodstream, so peripheral immune changes serve as an acceptable surrogate for intracranial activity.”
The study’s primary endpoint was progression-free survival compared to case-matched controls of patients treated with TTFields and temozolomide alone. Secondary endpoints included overall survival, response rate, safety parameters, as well as immune signature of response.
The combination of TTFields and Keytruda yielded particularly remarkable results in patients with bulky, biopsy-only tumors. Compared to controls, the test cohort achieved a median overall survival increase of 10 months (from a 14.6-month median in the control group to a 24.8-month median in the test group). “In glioblastoma, a 10-month improvement over standard chemotherapy is unprecedented,” Tran observes.
He notes the most striking benefit was seen in biopsy-only patients: “Their median survival was 31.6 months compared to only 18.8 months for maximum-resection patients — a 14-month, or more than one-year, advantage.”
Although both biopsy-only and maximum-resection patients benefited, those with more residual tumor achieved the greatest responses. Tran explains that TTFields require a sufficient tumor burden in the brain to provoke a robust immune reaction.
This makes this treatment approach particularly encouraging for patients with bulky, inoperable tumors — who typically face the poorest prognosis because their disease cannot be fully resected. “It seems for in situ immunization, a larger tumor burden can actually be advantageous,” Tran explains. “In our trial, biopsy-only patients responded more robustly, generating a much stronger memory immune response, and lived longer than those whose tumors were surgically removed.”
“Do we have data strong enough to shift the surgical management of brain tumors?” he asks. “The answer is currently no. However, data from this trial and other in situ immunization approaches suggest that if a tumor is abutting a critical brain region, and resection risks injury, it may be preferable to remove only the safely accessible portion and leave the remaining tumor to serve as a focal point for an immune reaction that makes immunotherapy possible.”
“Since the trial’s completion, we have treated several patients with large, unresectable brain tumors — and many are living far longer than expected,” he adds.
TTFields stands out because the device itself is patient-operated, giving individuals a greater sense of autonomy compared to other therapies, Tran notes.
“Cancer patients often feel their bodies are no longer under their own control, with infusions and procedures dictating their day,” he explains. “With the TTFields device, treatment happens at home, and patients can switch the device on or off as they choose.”
However, wearing the device for the prescribed duration is crucial for efficacy. Tran notes that most patients keep the arrays on for three to four consecutive days, including while sleeping. To maintain discretion, some use scarves or caps when out in public. As hair grows and prevents the electrode arrays from lying flat on the scalp, patients remove the arrays for several hours to one day and then reshave their head to apply a fresh electrode set. They can also plan around their social commitments — simply taking off the device on days they prefer not to wear it in public.
“As with any therapy,” Tran emphasizes, “if you don’t wear the device consistently, you won’t receive the correct dose, and it won’t work as effectively. In earlier pivotal trials, patients who maintained about 75% wear time over four weeks saw better outcomes. While we cannot yet define the exact minimum usage needed for maximal immune activation, our recommendation is to aim for as much daily use as possible — balanced with maintaining your quality of life — to generate a robust immunotherapy response.”
“Up to 20% of patients develop mild skin irritation from having the electrode arrays glued to the scalp,” Tran says. In those cases, the arrays can be repositioned to give affected areas a break from exposure, and topical steroids often provide relief.
Tran underscores, “The key takeaway from this study is that patients with large, bulky tumors tended to mount the most robust and durable responses to this treatment, suggesting that a greater tumor burden may help amplify the immune reaction.”
He continues: “Inducing a tumor-specific immune reaction is one thing, but enabling those same immune cells to home to the brain and infiltrate the tumor is another challenge entirely. For years, we’ve struggled to find a reliable, noninvasive way to accomplish that. With TTFields, we spark the anti-tumor immune reaction directly within the tumor. The local inflammation generated by TTFields transiently disrupts the blood-brain barrier, recruiting additional immune cells into the tumors. This creates a therapeutic window during which Keytruda can amplify the tumor-killing activity of both the immune cells already inside the tumors and those circulating in the bloodstream.”
A pivotal international Phase 3 trial is now underway to validate these findings. “If Phase 3 proves positive, it will become the definitive study that establishes this approach as the new standard of care,” Tran predicts.
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