Immunotherapy has revolutionized the treatment of many forms of cancer, but glioblastoma multiforme (GBM), the most common and deadly form of brain cancer, has not been touched. GBM tumors are sometimes called “cold” -; that is, the immune system has difficulty detecting and targeting them, allowing tumor cells to continue to grow uncontrollably, even with the advent of immunotherapy drugs. A study led by researchers at Brigham and Women’s Hospital presents a new approach to increasing heat and establishing an immunotherapy treatment to be successful. When the researchers used biodegradable implants loaded with a drug that can activate the STING – pathway; a known way to stimulate the immune system -; in preclinical models, they saw evidence of immune activity and a robust immune effect. Their findings, published in PNAS, suggest that activation of the STING pathway could help make GBM more susceptible to immunotherapy treatment.
“Glioblastoma tumors are resistant to therapies that work well in other cancers, so our goal here is to remove the shield that the tumor is using to protect itself,” said corresponding author Sean Lawler, PhD, formerly from Harvey Cushing Neuro-Oncology. Laboratories and the Brigham Department of Neurosurgery. Lawler is now at Brown University.
Our promising findings point to a new approach to using drug-laden brain implants to change the tumor microenvironment to support combination therapies, including immunotherapies. ”
E. Antonio Chiocca, MD, PhD, co-author, president of the Department of Neurosurgery, Brigham and Women’s Hospital
The STING pathway is called the interferon gene stimulator protein (STING), which is essential for helping cells detect pathogens and cancer cells. Although STING is well known, it had not been examined in detail in the context of GBM. One of the challenges of GBM treatment is that tumors hide behind the blood-brain barrier (BBB), which prevents drugs from crossing the circulating blood into the fluid of the central nervous system. To overcome this delivery challenge, researchers from Brigham’s Department of Neurosurgery collaborated with experts from the Wyss Institute, who developed a biocompatible hydrogel that could be loaded with a drug that activates STING and is released over time. . If successful, this hydrogel could be implanted directly into the brain during surgery to remove a patient’s tumor.
“Here we show that activation of the STING pathway completely reshapes the immune environment of the tumor and attracts cells that will shed in mice and produce long-term immunity against relapse. We were even more excited to see that the explants of human GBM respond to STING agonists by secreting a wide range of cytokines, demonstrating that the pathway is active in human tumors and can be used as a new approach to allow immunotherapy to work in GBM, ”said the first and co-author Gilles Berger, PharmD-PhD. , now an associate professor at the University of Brussels, Belgium.
The team tested this approach on GBM mouse models, finding that the treatment promoted long-term survival and immune memory. In the paper, they describe a change in the immune landscape of the tumor after treatment, with an influx of innate immune cells including inflammatory macrophages, neutrophils, and natural killer (NK) cells. Subsequent experiments showed that NK cells were critical -; depletion of these cells decreased the response.
The authors note that while their findings are promising, the stimulation of a strong immune response in the brain should be done with great caution. The study is an important principle test, but more refinement, optimization and rigorous testing of the ice delivery system are needed. The authors also want to test different drug combinations to determine which approach may be most effective.
Lawler attributes the progress so far to collaboration between neurosurgeons, cancer researchers and biomedical engineers.
“It’s a team science lesson,” he said. “We knew this was an interesting path, we found the right people to develop the initial tools and we turned to collaborators from the Dana-Farber Cancer Institute and the Wyss who were sources of great knowledge. This has been a puzzle and the next piece will be the clinical collaboration to bring it closer to patient care. “
Source:
Brigham and Women’s Hospital
Magazine reference:
Berger G et al. “STING activation promotes a robust immune response and NK cell-mediated tumor regression in glioblastoma models” PNAS DOI: 10.1073 / pnas.2111003119