Immune checkpoint inhibitors, medications that allow the body’s own immune system, particularly cancer-fighting T-cells, to recognize, find and attack tumor cells, can help stop the recurrence of cancer in many parts of the body.  

However, these drugs are not usually effective on brain cancers like astrocytoma due to the blood-brain barrier — a tightly sealed layer of cells that acts as a protective boundary between the brain and the bloodstream. Because this barrier is so effective, it also limits the ability of immune cells, including cancer-fighting T-cells, to enter the brain and reach the tumor.  

But now, Keck Medicine of USC researchers may have discovered a way to break through this blood-brain barrier and make immune checkpoint inhibitors effective for patients with recurrent, high-grade astrocytoma, thus potentially extending patients’ lives.   

Stunning results 

In a Phase 1/2b clinical trial, investigators combined a minimally invasive procedure that uses laser heat to both destroy the tumor tissue and disrupt the blood-brain barrier, with a common immune checkpoint inhibitor drug, pembrolizumab. 

The results, published today in Nature Communications, were striking. Nearly half of patients treated with laser interstitial thermal therapy (LITT), followed by pembrolizumab were still alive at 18 months. In comparison, none of the patients who received a conventional treatment of surgery followed by pembrolizumab were alive at the 18-month-mark.  

In addition, more than one-third of patients treated with LITT and the immune checkpoint inhibitor lived more than three years, far exceeding the typical four-to-five-month survival for patients with recurrent high-grade astrocytoma. 

“These results suggest that LITT can help the immune checkpoint inhibitor pembrolizumab work more effectively against high-grade astrocytoma,” said David Tran, MD, PhD, chief of neuro-oncology with Keck Medicine, co-director of the USC Brain Tumor Center and lead author of the study. “Patients with this type of advanced cancer have few remaining options and poor outcomes, and this approach could meaningfully extend their survival time and provide new hope for patients and their loved ones.” 

How LITT breaks through the blood-brain barrier  

Tran and his colleagues based the study on their past research showing that the heat produced by LITT can disrupt the blood–brain barrier for several weeks, which is enough time for T-cells to detect and target cancer cells once they have been activated by an immune checkpoint inhibitor.  

During the trial, participants received either LITT or surgery/biopsy, then the pembrolizumab. For those receiving LITT, neurosurgeons used magnetic resonance imaging (MRI) to locate the tumor in the brain, guide the LITT probe into the tumor, then precisely deliver laser heat to the tumor. The heat destroys the tumor while surgeons work to ensure no healthy brain tissue is damaged; and as a side product, the heat disrupts the blood-brain barrier.  

Once patients receive the immune checkpoint inhibitor, this disruption allows tumor materials to slip past the blood-brain barrier and into the blood. “This alerts T-cells to the presence of the tumor and provides easy passage of these T-cells to rush in, find and attack the tumor,” said Tran.  

About the clinical trial  

Forty-five patients enrolled in the study. All trial participants were in their second recurrence of astrocytoma, with nearly 15% in their third recurrence, meaning the cancer was at a very advanced stage. 

The LITT plus pembrolizumab combination was found to be generally safe and well-tolerated. 

Since the trial began, the U.S. Food and Drug Administration has cleared LITT for treating certain brain tumors, and pembrolizumab has been approved for several cancers.  

Keck Medical Center of USC was one of the three clinical trial sites nationwide, alongside researchers from Washington University in St. Louis and the University of Florida.  

Other USC authors for the study include Son B. Le, PhD, assistant professor of research neurological surgery at the Keck School of Medicine of USC; Harshit Manektalia, MS, computational research scientist at the Keck School; and Dongjiang Chen, MD, assistant professor of research neurological surgery at the Keck School. 

Parkinson’s disease is associated with reduced dopamine release in the brain. Dopamine is a neurotransmitter essential for movement, memory, mood and other functions. Research has shown that the tremors, stiffness, slow movement and other symptoms of Parkinson’s disease are caused by the progressive loss of dopamine-producing brain cells, disrupting the brain’s ability to regulate movement. 

Keck Medicine of USC is conducting an early phase clinical trial investigating the safety and effectiveness of implanting specialized stem cells into the brain that have been programmed to replace damaged brain cells and produce dopamine.  

“If the brain can once again produce normal levels of dopamine, Parkinson’s disease may be slowed down and motor function restored,” said Brian Lee, MD, PhD, a neurosurgeon with Keck Medicine and principal investigator of the study. 

Click here for seven warning signs of Parkinson’s disease

Unique stem cell therapy 

The therapy is a relatively new type of lab-generated stem cell called induced pluripotent stem cells (iPSCs). Unlike embryonic stem cells, iPCSs are adult cells, such as skin or blood cells, reprogrammed to a "blank slate" state capable of evolving into any type of cell. 

“We believe that these iPSCs can reliably mature into dopamine-producing brain cells, and offer the best chance of jump-starting the brain’s dopamine production,” said Xenos Mason, MD, a neurologist who specializes in Parkinson’s disease and other movement disorders with Keck Medicine and co-principal investigator of the study.  

During the procedure, Lee drills a small hole in the patient’s skull to access the brain, then precisely implants the stem cells into the basal ganglia, a part of the brain that controls movement, under the guidance of magnetic resonance imaging (MRI). 

After surgery, patients are monitored for 12-15 months for any changes in their Parkinson’s disease symptoms and for possible side effects including dyskinesia — excess movements — or infection. The doctors will continue to monitor the patients and their Parkinson’s disease symptoms for up to five years. 

“Our ultimate goal is to pioneer a technique that can repair patients’ motor function and offer them a better quality of life,” said Lee. 

Keck Medicine is one of three organizations in the United States participating in the clinical trial. The multisite study includes a total of 12 participants with moderate to moderate-severe Parkinson’s disease. 

This announcement is intended to share information about Keck Medicine’s research involvement and is not soliciting participants. 

The study finds that using Tumor Treating Fields therapy (TTFields), which delivers targeted waves of electric fields directly into tumors to stop their growth and signal the body’s immune system to attack cancerous tumor cells, may extend survival among patients with glioblastoma, when combined with immunotherapy (pembrolizumab) and chemotherapy (temozolomide).

TTFields disrupt tumor growth using low-intensity, alternating electric fields that push and pull key structures inside tumor cells in continually shifting directions, making it difficult for the cells to multiply. Preventing tumor growth gives patients a better chance of successfully fighting the cancer. When used to treat glioblastoma, TTFields are delivered through a set of mesh electrodes that are strategically positioned on the scalp, generating fields at a precise frequency and intensity focused on the tumor. Patients wear the electrodes for approximately 18 hours a day.

Researchers observed that TTFields attract more tumor-fighting T cells, which are white blood cells that identify and attack cancer cells, into and around the glioblastoma. When followed by immunotherapy, these T cells stay active longer and are replaced by even stronger, more effective tumor-fighting 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,” 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.”

TTFields are often combined with chemotherapy in cancer treatment. However, even with aggressive treatment, the prognosis for glioblastoma remains poor. Immunotherapy, while successful in many other cancer types, has also not proved effective for glioblastoma when used on its own.

However, in this study, adding immunotherapy to TTFields and chemotherapy was associated with a 70% increase in overall survival. Notably, patients with larger, unresected (not surgically removed) tumors showed an even stronger immune response to TTFields and lived even longer. 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.  

Using alternating electric fields to unlock immunotherapy

Pembrolizumab, the immunotherapy used in this study, is an immune checkpoint inhibitor (ICI), which enhances the body’s natural ability to fight cancers by improving T cells’ ability to identify and attack cancer cells.

However, there are typically few T cells in and around glioblastomas because these tumors originate in the brain and are shielded from the body’s natural immune response by the blood-brain barrier. This barrier safeguards the brain by tightly regulating which cells and substances enter from the bloodstream. Sometimes, this barrier even blocks T cells and other therapies that could help kill brain tumors.

This immunosuppressive environment inside and around the glioblastoma is what makes common cancer therapies like pembrolizumab and chemotherapy significantly less effective in treating it. Tran theorized the best way to get around this issue was to start an immune reaction directly inside the tumor itself, an approach known as in situ immunization, using TTFields.

This study demonstrates that combining TTFields with immunotherapy triggers a potent immune response within the tumor — one that ICIs can then amplify to bolster the body’s own defense against cancer.

“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, who is also a member of the USC Norris Comprehensive Cancer Center.

Study methodology and results

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 those, 26 received TTFields combined with both chemotherapy and immunotherapy. Seven of these 26 patients had inoperable tumors due to their locations — an especially high-risk subgroup with the worst prognosis and few treatment options.

Patients in the trial were given six to 12 monthly treatments of chemotherapy alongside TTFields for up to 24 months. The number and duration of treatments were determined by patients’ response to treatment. The immunotherapy was given every three weeks, starting with the second dose of chemotherapy, for up to 24 months.

Patients who used the device alongside chemotherapy and immunotherapy lived approximately 10 months longer than patients who had used the device with chemotherapy alone in the past. Moreover, 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.

“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.

Moving the research forward

Keck Medicine is participating in the multicenter Phase 3 clinical trial to validate the efficacy of TTFields with immunotherapy and chemotherapy. Tran, who has been researching TTFields for more than a decade, serves as the chair of the steering committee for this trial. Frances Chow, MD, neuro-oncologist with USC Norris, is the principal investigator of the Keck Medicine study site.

This Phase 3 trial, currently open at 28 sites across the United States, Europe and Israel, aims to enroll over 740 patients through April 2029, including those with gross total resection, partial resection or biopsy-only tumors to assess the extent of how surgically removing tumors influences immune response.

Traditionally, stroke patients try to regain motor function through physical rehabilitation, where patients re-learn pre-stroke skills, such as eating motions and grasping. However, most patients eventually plateau and stop improving over time.

Now, results of a clinical trial published in The Lancet gives patients new hope in their recovery.

Patients who received a novel treatment that combines vagus nerve stimulation (VNS) and rehabilitation showed improvement in upper body motor impairment compared to those who received sham (inactive form of) stimulation and rehabilitation. Considered a natural antenna to the brain, the vagus nerve runs from the chest and abdomen to the brainstem and regulates many of the body’s functions.

“This is incredibly exciting news for everyone involved in stroke rehabilitation and functional restoration and represents a unique intersection between neurosurgery and neurorehabilitation,” said Charles Liu, MD, PhD, the lead neurosurgeon of the study and director of the USC Neurorestoration Center of Keck Medicine of USC. “These study results are the first of their kind, and open up new possibilities for stroke patients, allowing them to reclaim more arm function even years after having a stroke.”

In this international, multi-center clinical trial, 53 participants with moderate to severe arm weakness nine months to 10 years post-stroke, received rehabilitation paired with VNS. Fifty-five patients within the same parameters received a sham stimulation. The trial was randomized and triple blind.

Those receiving the nerve stimulation had a wire inserted into their neck that wrapped around the vagus nerve. The wire was then connected to a pulse generator device implanted in the chest. Those receiving the sham received placebo implants.

After the surgical procedure, all patients received six weeks of in-clinic therapy, which included tasks such as reaching and grasping, simulated eating and opening and closing containers. After the in-clinic period, patients continued treatment with a course of daily home therapy.

When the two patient groups were compared, those receiving the nerve stimulation scored higher on several standardized measures of upper arm functionality.

“Not only were the results clinically meaningful, the fact that these patients were at least nine months post-stroke and in some instances years out, points to the possibility that meaningful improvements can be achieved even years after a stroke,” said Liu, who also serves as chief of innovation and research and chair of neurosurgery and orthopedics at Rancho Los Amigos National Rehabilitation Center.

The device is thought to work by triggering the release of brain neuromodulators – which regulate the body’s responses – to strengthen motor circuits in the brain associated with movement, enabling the brain to effectively relearn tasks. VNS is already used widely for the treatment of epilepsy and plays an increasing role in the treatment of severe depression.

“For too long, stroke patients have faced limited options for recovery,” said Liu. “This new treatment signifies a breakthrough that could be life-changing for many stroke patients and also represents an approach that will certainly be explored for many other functional restoration applications in the future.”

The VNS system utilized for the study is owned by MicroTransponder Inc., a medical device development company, who sponsored the study.

Lead authors on the study include Jesse Dawson, MD, College of Medical, Veterinary and Life Sciences, University of Glasgow in Scotland; Teresa J. Kimberley, PhD, Massachusetts General Hospital; and Navzer Engineer, MD, PhD, of MicroTransponder Inc.

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For more information about Keck Medicine of USC, please visit news.KeckMedicine.org.

To help Californians receive the highest level of care regardless of where they live, epilepsy experts have established the USC Epilepsy Care Consortium, a unique partnership of six independent comprehensive epilepsy centers serving patients in Los Angeles County, Orange County and the Central Valley. Keck Medicine of USC serves as the academic medical center and anchor of the consortium.

Charles Liu, MD, PhD, and Christianne Heck, MD, who serve respectively as surgical and medical director for the USC Comprehensive Epilepsy Center, sought to collaborate with other institutions after noticing that patients often drove for hours to seek services at the Center because their local hospitals did not offer epilepsy care.

“Many patients were burdened with long travel times, and we were concerned that those without the means to travel were not getting treatment,” says Heck, professor of clinical neurology at the Keck School of Medicine of USC. “We realized we needed to join forces with other hospitals to help build additional epilepsy programs and provide them with access to ours.”

The two physicians, who also direct and co-direct the USC Neurorestoration Center, along with support from fellow USC Neurorestoration Center doctors, created a network of collaborating epilepsy centers spanning a variety of medical settings: public and private, adult and pediatric, urban and rural.

The USC Comprehensive Epilepsy Center, a National Association of Epilepsy Centers accredited level 4 center — the highest level possible — acts as the hub of the consortium. Patients with complex cases that require advanced treatments or surgeries that can’t be addressed at a collaborating hospital can be treated at Keck Medical Center of USC.

Consortium members share cases and recommendations through weekly teleconferences. They track patients’ progress through a shared electronic data reporting system, resulting in a network-based system of care for each patient.

“The consortium is a bold and exciting initiative that offers patients the combined resources and expertise of six different centers,” says Liu, professor of clinical neurological surgery at the Keck School. “Patients can take advantage of the top technology and treatments available in the field, as well as the combined collective wisdom of multiple epilepsy experts.”

Epilepsy, a brain disorder marked by seizures due to abnormal electrical activity in the brain, is one of the most common neurological disorders worldwide. Without treatment, those with epilepsy are at greater risk for seizure-related accidents, such as falling, as well as a fatal complication known as sudden unexplained death in epilepsy, when patients die for no known cause. Untreated epilepsy also can lead to greater rates of unemployment and depression because seizures, which often cannot be anticipated, may interfere with holding down a job and enjoying life.

In addition to the USC Comprehensive Epilepsy Center, other participating institutions in the consortium include Children’s Hospital Los Angeles, Rancho Los Amigos National Rehabilitation Center in Downey, Hoag Hospital in Newport Beach, Kern Medical Center in Bakersfield and Valley Children’s Healthcare in Madera.

Building the skills needed to treat complex neurological conditions like stroke, brain tumors or spinal cord injuries requires a highly demanding, seven-year training program. The pressure of that training can sometimes lead to emotional exhaustion, an inability to connect with others or feeling unaccomplished, which are components of burnout. Understanding what factors influence burnout can be a powerful catalyst for change.
“As a patient, you don’t want your doctor to be depressed or demoralized when they’re working on you, because they’re not their best self,” said the study’s lead author Frank Attenello, MD, MS, assistant professor of clinical neurological surgery at the Keck School. “And as a society, we don’t want to discourage people from becoming neurosurgeons, because we have a rapidly aging population in need of neurosurgeons’ skills.”
While research on burnout is gaining steam in many fields, not much attention has been paid to it in neurosurgery until now, Attenello explained.
To better understand it, Attenello and his colleagues surveyed 346 neurosurgery residents across the United States. Using an 86-item questionnaire, the team explored everything from whether residents felt satisfied with different aspects of their training to whether they were considering quitting training or leaving medicine entirely. Burnout was assessed using the Maslach Burnout Inventory, a validated tool that has been used to measure burnout both in health care and other professions.

The study, published Feb. 9 in the Journal of Neurosurgery, found that 81 percent of residents were satisfied with their career, but 41 percent had given serious thought to quitting neurosurgery at some point. The overall burnout rate was 67 percent — more than double the estimated rate of burnout among American workers overall. Predictors of burnout included inadequate exposure to the operating room, hostile faculty, unsatisfactory relationships with mentors and social stressors outside of work.

“Some of the most impressive and energetic medical students enter neurosurgery,” Attenello said. “When they encounter burnout, it limits their considerable potential, both with their patient care and possibly in their academic and research achievements for the field as a whole.”
To help reduce the risk of burnout, Attenello and others at the Keck School have already implemented a new model for mentorship. This year, new residents in the Department of Neurological Surgery will choose their mentors and the school will assign a backup mentor for additional support.

“Our study provided some valuable insights to the prevalence of burnout and some of the pain points in training neurosurgeons,” said study co-author Steven L. Giannotta, MD, chair and professor of neurological surgery at the Keck School. “Recognizing that burnout exists and finding ways to address it are important steps educational institutions can take to mitigate it.”

— Erica Rheinschild