By Billy Candra 
A groundbreaking study led by researchers at Keck Medicine of USC has unveiled a promising new combination therapy that could dramatically alter the bleak prognosis for glioblastoma, an aggressive and notoriously difficult-to-treat brain cancer. This novel approach, integrating Tumor Treating Fields (TTFields) therapy with both immunotherapy (pembrolizumab) and chemotherapy (temozolomide), demonstrated a significant increase in overall survival for patients, particularly those with larger, inoperable tumors. This finding offers a beacon of hope in a field where effective treatments are scarce, and the average survival for diagnosed patients typically hovers around eight months, according to the National Brain Tumor Society.
The study, a Phase 2 clinical trial known as 2-THE-TOP, suggests that this synergistic triple-modality regimen could be the key to unlocking the full potential of immunotherapy in glioblastoma, a challenge that has long stymied neuro-oncologists. By strategically combining these therapies, researchers appear to have found a way to "prime" the tumor environment, making it more susceptible to the body’s own immune defenses.
Glioblastoma: A Formidable and Elusive Foe
Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor in adults, classified as a Grade IV astrocytoma. Its devastating nature stems from several inherent characteristics. GBM tumors are highly infiltrative, meaning their cells spread quickly into surrounding healthy brain tissue, making complete surgical resection exceedingly difficult, if not impossible. This infiltrative growth also contributes to a high rate of recurrence, even after seemingly successful initial treatment.
The incidence of glioblastoma is approximately 3.21 cases per 100,000 population in the United States, affecting thousands annually. Despite advances in neurosurgery, radiation therapy, and chemotherapy, the median overall survival for newly diagnosed glioblastoma patients has remained stubbornly low, often ranging from 12 to 15 months with aggressive standard-of-care treatment. For patients whose tumors cannot be surgically removed, the prognosis is even grimmer.
A significant hurdle in treating glioblastoma is the blood-brain barrier (BBB). This highly selective semipermeable membrane protects the brain from circulating toxins and pathogens but also effectively blocks many therapeutic agents, including some chemotherapy drugs and immune cells, from reaching the tumor in sufficient concentrations. Furthermore, glioblastomas create a profoundly immunosuppressive microenvironment, actively recruiting and activating cells that suppress the immune response, making it incredibly difficult for the body’s natural defenses to recognize and attack the cancer cells. This "cold" tumor environment has been a primary reason why immunotherapies, which have revolutionized the treatment of many other cancers, have largely failed as monotherapies in glioblastoma.
The Evolving Landscape of Glioblastoma Treatment
For decades, the standard of care for newly diagnosed glioblastoma has involved maximal safe surgical resection, followed by radiation therapy concomitant with and then adjuvant temozolomide (TMZ). Temozolomide, an oral alkylating chemotherapy agent, works by damaging the DNA of cancer cells, inhibiting their growth. While this regimen has been shown to extend survival by approximately 2.5 months compared to radiation alone, the overall outcome remains poor, underscoring the urgent need for more effective strategies.
Tumor Treating Fields (TTFields) therapy represents a more recent addition to the glioblastoma treatment arsenal. Approved by the FDA for recurrent glioblastoma in 2015 and then for newly diagnosed glioblastoma in combination with temozolomide in 2015, TTFields (marketed as Optune by Novocure) utilizes low-intensity, intermediate-frequency alternating electric fields delivered directly to the tumor via transducer arrays placed on the patient’s scalp. These electric fields disrupt key cellular processes necessary for cancer cell division, specifically mitosis, by pushing and pulling critical structures inside tumor cells in continually shifting directions. This mechanical interference prevents tumor cells from multiplying effectively, slowing tumor growth and potentially leading to cell death. Patients typically wear the device for approximately 18 hours a day.
Immunotherapy, specifically immune checkpoint inhibitors (ICIs) like pembrolizumab, works by unleashing the body’s own immune system to fight cancer. These drugs block proteins (checkpoints) that normally put the brakes on immune cells, particularly T cells, allowing them to identify and attack cancer cells more effectively. While ICIs have achieved remarkable success in treating melanoma, lung cancer, kidney cancer, and other malignancies, their efficacy in glioblastoma has been limited when used alone due to the aforementioned immunosuppressive tumor microenvironment and the blood-brain barrier.
A Synergistic Attack: Unlocking Immunotherapy with TTFields
The 2-THE-TOP study hypothesized that combining TTFields with both chemotherapy and immunotherapy could overcome the inherent resistance of glioblastoma to immune-based treatments. Dr. 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, theorized that the best way to circumvent the glioblastoma’s immunosuppressive environment was to initiate an immune reaction directly within the tumor itself—an approach known as in situ immunization—using TTFields.
The findings from the study strongly support this theory. Researchers observed that TTFields not only disrupt tumor growth but also attract a greater number of tumor-fighting T cells, a type of white blood cell crucial for immune response, into and around the glioblastoma. This influx of T cells, coupled with the direct cellular disruption caused by TTFields, effectively makes the tumor more "visible" and vulnerable to the immune system. When followed by immunotherapy like pembrolizumab, these T cells remain active for longer periods and are replaced by even stronger, more effective anti-tumor T 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," explained Dr. Tran. "Our findings suggest that TTFields may be the key to unlocking the value of immunotherapy in treating glioblastoma." He further elaborated on this synergistic effect using a sports analogy: "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."
This combination therapy creates a potent immune response within the tumor that immune checkpoint inhibitors can then amplify, bolstering the body’s own defense mechanisms against the cancer.
Study Methodology and Remarkable Results
The 2-THE-TOP study was a Phase 2 clinical trial that enrolled 31 newly diagnosed glioblastoma patients who had completed initial chemoradiation therapy. Of this cohort, 26 received the triplet therapy: TTFields combined with both chemotherapy (temozolomide) and immunotherapy (pembrolizumab). A critical subgroup within these 26 patients were those with inoperable tumors due to their location—a population historically facing the direst prognosis and severely limited treatment options. Seven patients fell into this high-risk category.
Patients in the trial received between six to twelve monthly cycles of temozolomide alongside continuous TTFields therapy for up to 24 months, with the duration determined by individual patient response. Pembrolizumab was administered every three weeks, starting with the second dose of chemotherapy, also for up to 24 months.
The results were compelling. Patients who underwent the triplet therapy lived approximately 10 months longer than patients who had historically used TTFields with chemotherapy alone. This represents a significant 70% increase in overall survival, a remarkable improvement in a disease where incremental gains are hard-won.
Even more striking were the findings for patients with large, inoperable (unresected) tumors. This subgroup, traditionally associated with the worst outcomes, lived approximately 13 months longer with the triplet therapy and exhibited a much stronger immune activation compared to patients who underwent surgical removal of their tumors. This counter-intuitive finding suggests that for initiating an immune response against glioblastoma, a larger tumor might paradoxically provide more targets for the therapy to work against, potentially making it more immunogenic when subjected to TTFields.
"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," Dr. Tran noted. This opens up an entirely new avenue of discussion regarding the sequencing and necessity of extensive surgical resection in all glioblastoma cases, especially if an effective immune-priming strategy is available.
The Road Ahead: Validating Efficacy in Phase 3
Building on the promising results of the 2-THE-TOP study, Keck Medicine of USC is actively participating in a multicenter Phase 3 clinical trial, known as TRIDENT, to definitively validate the efficacy and safety of TTFields in combination with immunotherapy and chemotherapy. Dr. Tran, who has dedicated over a decade to researching TTFields, serves as the chair of the steering committee for this pivotal trial. Dr. Frances Chow, a neuro-oncologist with USC Norris, is the principal investigator of the Keck Medicine study site.
The TRIDENT trial is a global undertaking, currently open at 28 sites across the United States, Europe, and Israel. It aims to enroll over 740 patients through April 2029. Crucially, this large-scale trial will include patients with varying degrees of surgical intervention—gross total resection, partial resection, or biopsy-only tumors—to thoroughly assess how the extent of tumor removal influences the immune response and overall patient outcomes. The robust design of a Phase 3 trial is essential to confirm the earlier findings and establish this combination therapy as a new standard of care.
Broader Implications and Expert Perspectives
The implications of this research extend far beyond the immediate survival benefits for glioblastoma patients. It offers a paradigm shift in understanding how to effectively harness the immune system against brain tumors. For years, the brain has been considered an "immune-privileged" site, largely shielded from systemic immune responses. This study challenges that notion, demonstrating that with the right combination of therapies, it is possible to overcome the natural barriers and activate a robust anti-tumor immune response within the brain itself.
Patient advocacy groups, like the National Brain Tumor Society, will undoubtedly follow the progress of the TRIDENT trial closely. Any significant improvement in glioblastoma survival would represent a monumental victory for patients and their families who currently face such limited options. The potential for improved quality of life and extended survival, especially for those with inoperable tumors, offers a renewed sense of hope.
However, the widespread adoption of such a complex regimen will also present challenges. TTFields therapy requires significant patient adherence, with electrodes needing to be worn for extended periods daily. The cost of these advanced therapies, including pembrolizumab and TTFields, will also be a factor in accessibility and healthcare economics. Further research will be critical to identify optimal patient selection biomarkers, refine treatment durations, and explore potential synergies with other emerging therapies.
The study’s authors from Keck School of Medicine of USC include Dongjiang Chen, PhD, assistant professor of research neurological surgery; Son Le, PhD, assistant professor of research neurological surgery; Harshit Manektalia, research programmer; Ming Li, PhD, professor of research population and public health sciences; and Adam O’Dell, research lab specialist. Ashley Ghiaseddin, MD, and Maryam Rahman, MD, MS, from the University of Florida, also contributed to this significant work.
It is important to note that this study was funded by a grant from Novocure, the manufacturer of Optune, the TTFields device used in the research. Dr. Tran has received honoraria from Novocure for consultant work, and both Dr. Chen and Dr. Tran are inventors of two patent applications related to the work reported in this study. This disclosure ensures transparency regarding potential conflicts of interest, a standard practice in medical research. The ongoing Phase 3 trial, with its larger scope and independent validation, will be crucial in solidifying these promising early findings and potentially ushering in a new era of glioblastoma treatment.
