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Immunotherapy before surgery?
March 2019
by Jeffrey Bouley  |  Email the author
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HOUSTON & LOS ANGELES—While glioblastoma is the most common, most aggressive and deadliest form of brain cancer, its primacy hasn’t translated into a great many therapeutic options. Tumor heterogeneity and the challenges of getting drugs past the blood-brain barrier make it difficult to treat glioblastoma, and thus median overall survival for primary glioblastoma is 14.6 months with the standard treatments of surgery, radiation therapy and the chemotherapy temozolomide—falling to 5.5 to 11 months for recurrent glioblastoma.
 
While immunotherapies such as immune checkpoint inhibitors—and the promising research results around them for some cancers, like leukemia and melanoma—are giving researchers, clinicians and patients increasing hope for effective therapies, this area of study and treatment is still a new one.
 
A recent clinical trial could be a boost for those hopes. Results from a recent study conducted by researchers at the University of California, Los Angeles, and six other participating institutions, including The University of Texas MD Anderson Cancer Center, are offering encouragement for the use of immunotherapy in helping these patients, as noted in an article by Dr. Jill Russell on the MD Anderson website.
 
Published early this year in Nature Medicine, the study indicates that patients who were given the immune checkpoint inhibitor pembrolizumab before glioblastoma surgery lived on average twice as long as those given the PD-1 inhibitor after surgery.
 
According to Russell, it is “the first study to show survival benefit for patients with glioblastoma who received neoadjuvant pembrolizumab, which blocks programmed cell death protein 1, also known as PD-1. PD-1 helps regulate the immune system’s response to avoid autoimmunity, but also can prevent the immune system from targeting cancer cells.”
 
The randomized, open-label study included 35 patients with recurrent, surgically resectable glioblastoma. Sixteen patients received two doses of pembrolizumab before surgery and continued to receive pembrolizumab after surgery (neoadjuvant group), and 19 patients received pembrolizumab only after surgery (adjuvant group).
 
“This study could change the way we treat patients with recurrent glioblastoma,” says Dr. John de Groot, an author of the study and interim chair of neuro-oncology at MD Anderson. “One of the surprising aspects of this study was that most patients in the neoadjuvant group benefited, so it is unlikely that these results were due to chance. Our findings need to be validated, but it appears that neoadjuvant pembrolizumab could work for a broad group of patients.”
 
Added Russell in her article, pembrolizumab has shown survival benefit in several other cancer types, but primarily as an adjuvant monotherapy. But recent studies in metastatic breast cancer, resectable lung cancer and melanoma have shown that neoadjuvant checkpoint inhibitors can increase antitumor immune responses compared to the same drugs used in an adjuvant setting.
 
As of the analysis cutoff date (July 2, 2018), patients in the neoadjuvant group had a median overall survival of 417 days (13.7 months), which was significantly longer than the adjuvant group (228 days [7.5 months]). Patients in the neoadjuvant group did not experience new toxicities, and many of the adverse events that were reported during the study are frequently experienced by patients with central nervous system tumors and/or those who have received corticosteroids.
 
The study also used T cell receptor sequencing, gene expression profiling, quantitative multiplex immunofluorescence and mass cytometry to analyze tumor tissue samples from the patients to determine pembrolizumab’s mechanisms of action. The findings suggest that neoadjuvant pembrolizumab initiates a local and systemic T cell response. Pembrolizumab systemically activates tumor-infiltrating lymphocytes, which increases transcription of genes related to interferon gamma and inhibits the transcription of tumor cell-cycle genes (thus inhibiting tumor cell proliferation). Pre-surgical checkpoint inhibition increases tumor-specific T cells; if the tumor has already been resected, the immune system produces fewer tumor-specific T cells and residual tumor cells proliferate more rapidly.
 
The study’s findings also suggest that T cell receptor diversity may help sustain the immune system’s ability to attack tumor cells, so the researchers plan to combine neoadjuvant pembrolizumab with a CTLA-4 checkpoint inhibitor, which has been shown to promote the diversity of T cell receptors in patients with melanoma. CTLA-4 inhibition has not been investigated in the neoadjuvant setting, but as with pembrolizumab, timing may prove important for CTLA-4’s efficacy in patients with recurrent glioblastoma.
 
In other news of cancer, the brain and immunotherapy from MD Anderson, the center talked about how melanoma tumors that have spread to the brain are equipped to thwart immunotherapies and targeted therapies that succeed against tumors growing in other sites, noting that some of its researchers reported in Cancer Discovery that the heavy reliance of these tumors on a specific metabolic pathway presents a potential new therapeutic target against these lethal tumors.
 
The team’s in-depth analysis of brain metastases and comparison of those tumors to others that had spread to different parts of the body was the first such application of advanced RNA sequencing, and uncovered a variety of factors that make tumors in the brain so difficult to treat.
 
“Brain metastases are increasingly recognized as one of our biggest challenges in cancer,” said senior author Dr. Michael Davies, an associate professor of melanoma medical oncology. “Melanoma patients with advanced disease have the highest risk of developing brain metastases among common solid tumors, and they are a leading cause of death from this disease. This research provides new insights into why these tumors may be worse, and it, importantly, found something that might be targetable—oxidative phosphorylation metabolism—with drugs that are in clinical trials now.”
 
As MD Anderson explains, cells generally rely heavily on two types of metabolism to survive. Mitochondria use oxygen to convert glucose, fatty acids and proteins into energy by a process of oxidative phosphorylation (OXPHOS). A more common form of metabolism in cancer is energy production by glycolysis, the conversion of glucose to energy in the absence of oxygen.
 
Analysis showed that genes involved in oxidative phosphorylation were upregulated in brain metastases, leaving those tumors reliant on that form of metabolism. Previous research by this team and others has also shown that OXPHOS promotes resistance to immunotherapies and targeted therapies.
 
The researchers found that brain metastases that form in mouse models of melanoma also develop high levels of OXPHOS activity.
 
IACS-10759, a drug that blocks OXPHOS and was developed by MD Anderson’s Institute for Applied Cancer Sciences (IACS), is in a Phase 1 clinical trial against blood cancers and solid tumors. IACS, focused on developing impactful small-molecule therapies, is part of MD Anderson’s Therapeutics Discovery Division.
 
The scientists found that treatment with IACS-10759 blocked brain metastases from forming in one mouse model that develops metastatic melanoma, but it had much less impact on primary tumor growth or on the development of lung metastases. Treatment with the drug increased survival of mice with existing brain metastases in other models.
 
“OXPHOS inhibition could be a whole new therapeutic strategy for treating these patients,” Davies said. MD Anderson researchers are working to develop clinical trials.
 
Code: E031903

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