By Lina carolina 
A groundbreaking study spearheaded by researchers at Keck Medicine of USC has unveiled a potentially transformative combination therapy for glioblastoma, a notoriously aggressive and difficult-to-treat brain tumor. For patients diagnosed with glioblastoma, the prognosis has historically been grim, with an average survival rate of a mere eight months, according to the National Brain Tumor Society. This new research suggests that integrating Tumor Treating Fields (TTFields) therapy with a regimen of immunotherapy and chemotherapy could offer a significant improvement in patient outcomes, marking a crucial step forward in the fight against this devastating disease.
Unlocking Immunotherapy’s Potential for Glioblastoma
The core of this innovative approach lies in the synergistic action of TTFields, a non-invasive treatment that uses targeted electrical fields to disrupt cancer cell growth, combined with pembrolizumab (an immunotherapy agent) and temozolomide (a chemotherapy drug). The study’s findings indicate that this multi-pronged strategy not only halts tumor progression but also primes the patient’s immune system to more effectively combat the cancer.
TTFields operate by generating low-intensity, alternating electric fields that are precisely delivered to the tumor site. These fields create a constant push-and-pull effect on crucial cellular structures within cancer cells, making it exceedingly difficult for them to divide and multiply. This disruption of tumor growth is a critical first step, providing a more favorable environment for the immune system and other therapies to exert their effects. In the context of glioblastoma, TTFields are administered through a series of mesh electrodes carefully positioned on the scalp, generating electrical fields at a specific frequency and intensity calibrated to target the tumor. Patients typically wear this device for approximately 18 hours a day, integrating it into their daily routines.
A key observation from the research is that TTFields appear to significantly increase the infiltration of tumor-fighting T cells – a vital component of the immune system responsible for identifying and neutralizing cancerous cells – into and around the glioblastoma. When this T-cell activation is followed by immunotherapy, such as pembrolizumab, these T cells not only remain active for longer periods but are also replenished by even more potent and effective tumor-fighting T cells.
Dr. David Tran, MD, PhD, chief of neuro-oncology at Keck Medicine, co-director of the USC Brain Tumor Center, and the study’s corresponding author, emphasized the revolutionary potential of this combination. "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," Dr. Tran explained. "Our findings suggest that TTFields may be the key to unlocking the value of immunotherapy in treating glioblastoma."
Historically, glioblastoma treatment has relied on a combination of surgery, radiation, and chemotherapy. While TTFields have often been used in conjunction with chemotherapy, the prognosis has remained bleak. Immunotherapy, despite its success in treating numerous other cancer types, has largely failed to demonstrate significant efficacy as a standalone treatment for glioblastoma. This new study, however, suggests that by combining TTFields with immunotherapy and chemotherapy, researchers have found a way to overcome these limitations.
A Significant Leap in Survival Rates
The results of the study are particularly compelling. The addition of immunotherapy to the TTFields and chemotherapy regimen was associated with a remarkable 70% increase in overall survival for patients. This is a substantial improvement in a disease where even incremental gains are considered significant.
Intriguingly, patients with larger, unresected (meaning not surgically removed) tumors exhibited an even more robust immune response to TTFields and experienced longer survival periods. This finding suggests that the presence of a larger tumor might, paradoxically, provide more targets for the therapy to engage with, thereby kick-starting a more vigorous immune response against the cancer. This observation has profound implications for treatment strategies, particularly for patients whose tumors are deemed inoperable due to their location or other factors.
The Mechanism: Overcoming the Brain’s Immune Defenses
The success of this combination therapy hinges on its ability to circumvent the unique challenges posed by glioblastoma, particularly its location within the brain and the protective blood-brain barrier. Pembrolizumab, the immunotherapy agent used in the study, functions as an immune checkpoint inhibitor (ICI). ICIs work by releasing the brakes on the immune system, enhancing the ability of T cells to recognize and attack cancer cells.
However, glioblastomas often exist in an environment with a scarcity of T cells. The brain’s inherent immune privilege, reinforced by the tightly regulated blood-brain barrier, often shields it from the body’s natural immune surveillance. This barrier, designed to protect the brain from harmful substances, can also inadvertently impede the entry of beneficial immune cells and therapeutic agents, including T cells and immunotherapy drugs, into the tumor site.
This immunosuppressive microenvironment within and around glioblastomas has been a major hurdle, rendering conventional therapies like pembrolizumab and chemotherapy less effective. Dr. Tran’s hypothesis was that the most effective strategy would be to initiate an immune reaction directly within the tumor itself – a concept known as in situ immunization. TTFields, through their unique mechanism of action, appear to achieve this, effectively "waking up" the local immune system.
The study’s findings support this theory, demonstrating that the combination of TTFields and immunotherapy effectively triggers a potent immune response within the tumor. This internally generated immune activity then primes the tumor microenvironment for ICIs like pembrolizumab to amplify the immune assault, thereby bolstering the body’s own defense mechanisms against the cancer.
Dr. Tran likened this process to a strategic team sport. "Immunotherapy sends players in to attack the tumor (the offense), while TTFields weaken the tumor’s ability to fight back (the defense)," he explained. "And just like in team sports, the best defense is a good offense." This analogy highlights how TTFields create a more vulnerable tumor, allowing the immunotherapy to be significantly more effective.
Study Design and Groundbreaking Results
The research meticulously analyzed data from the 2-THE-TOP Phase 2 clinical trial. This trial enrolled 31 patients newly diagnosed with glioblastoma who had already completed chemoradiation therapy. A significant majority of these patients, 26 in total, received TTFields in conjunction with both chemotherapy and immunotherapy. Notably, seven of these 26 participants had inoperable tumors due to their location, representing an exceptionally high-risk subgroup with the poorest prognoses and limited treatment options.
Participants in the trial underwent a treatment regimen that included six to 12 monthly cycles of chemotherapy, administered alongside TTFields for durations of up to 24 months. The exact number and length of treatment cycles were individualized based on each patient’s response. The immunotherapy, pembrolizumab, was administered every three weeks, commencing with the second dose of chemotherapy, and continued for up to 24 months.
The results were striking. Patients who utilized the TTFields device alongside chemotherapy and immunotherapy lived approximately 10 months longer than historical control groups who had received the device with chemotherapy alone. Furthermore, for the subgroup with large, inoperable tumors, the survival benefit was even more pronounced, with these patients living approximately 13 months longer and demonstrating significantly stronger immune activation compared to patients who underwent surgical tumor removal.
"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 commented, acknowledging the ongoing need to refine surgical approaches in light of these new therapeutic possibilities.
The Path Forward: Phase 3 Trials and Future Directions
Building on these encouraging results, Keck Medicine is actively involved in a multicenter Phase 3 clinical trial designed to rigorously validate the efficacy of TTFields in combination with immunotherapy and chemotherapy. Dr. Tran, who has dedicated over a decade to researching TTFields, is leading the steering committee for this pivotal trial. Dr. Frances Chow, a neuro-oncologist with USC Norris, serves as the principal investigator for the Keck Medicine study site.
This large-scale Phase 3 trial is currently underway at 28 sites across the United States, Europe, and Israel. It aims to enroll over 740 patients by April 2029. The trial’s comprehensive design includes patients with varying degrees of tumor resection – including gross total resection, partial resection, and biopsy-only tumors. This approach is crucial for assessing how the extent of surgical tumor removal might influence the immune response and overall treatment efficacy.
The collaborative efforts behind this research extend beyond Keck Medicine. Authors from the Keck School of Medicine of USC contributing to this study 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. Additionally, Ashley Ghiaseddin, MD, and Maryam Rahman, MD, MS, from the University of Florida, made significant contributions to this work.
Funding for this crucial research was provided by a grant from Novocure, the manufacturer of the Optune device, which delivers TTFields therapy. Dr. Tran has received honoraria from Novocure for his consultant work, and both he and Dr. Chen are listed as inventors on two patent applications related to the work presented in this study. These affiliations and contributions underscore the collaborative and industry-supported nature of advancing novel cancer therapies.
The implications of this research are far-reaching. For a disease with such a devastating prognosis and limited treatment options, the prospect of significantly extending survival and improving quality of life for glioblastoma patients represents a monumental achievement. The successful integration of TTFields with immunotherapy and chemotherapy could redefine the standard of care for glioblastoma, offering a renewed sense of hope to patients and their families worldwide. The ongoing Phase 3 trial will be instrumental in confirming these findings and potentially paving the way for broader clinical adoption of this promising combination therapy.
