Researchers are exploring a new method to make glioblastoma cells more susceptible to various forms of immunotherapy. This approach was tested in laboratory cells and aims to prompt brain cancer cells to showcase targets that the immune system can attack.
Despite receiving cutting-edge treatments, glioblastoma patients—who face an aggressive type of brain cancer—usually have a survival time of less than two years post-diagnosis. Attempts to use modern immunotherapies for this cancer have largely failed, likely because glioblastoma cells generally lack accessible targets for immune system intervention.
Researchers at Washington University School of Medicine in St. Louis conducted a cell-based investigation where they prompted glioblastoma cells to present immune system targets. This advancement could allow these cancer cells to become visible to immune cells, thereby increasing their susceptibility to immunotherapies. The method uses a combination of two already FDA-approved drugs, each aimed at treating different types of cancer.
The research is published in the journal Nature Genetics.
“For patients whose tumors don’t naturally generate targets for immunotherapy, we have demonstrated a method to induce their formation,” explained co-senior author Ting Wang, PhD, who leads the Department of Genetics at WashU Medicine. “In essence, if there’s no target, we can create one. This represents a novel approach to designing targeted and personalized cancer therapies. We are optimistic about progressing to clinical trials, combining immunotherapy with this technique to offer new treatment options for challenging cancers.”
Wang’s focus has been on transposable elements in DNA, which are segments that can move around within the genome. These elements are seen as a double-edged sword in cancer research. Wang’s findings suggest that while transposable elements contribute to tumor development, they also present potential vulnerabilities that could lead to innovative treatment strategies.
In this study, Wang’s team utilized transposable elements since they can cause tumors to produce unique proteins not found in healthy cells. These proteins, labeled tumor antigens or neoantigens, could serve as targets for various forms of immunotherapy, including checkpoint inhibitors and genetically modified T-cell therapies.
However, certain tumors, including glioblastoma, produce few natural immune targets from transposable elements. To overcome this limitation, Wang and colleagues, including co-senior author Albert H. Kim, MD, PhD, have discovered a method to deliberately stimulate transposable elements in glioblastoma cells that generally do not manufacture these targets.
The researchers used a pair of drugs that affect the epigenome, the regulatory layer that determines gene activity levels. The treatment of glioblastoma cells with these two epigenetic drugs led to the unwinding of tightly packed DNA, stimulating transposable elements to start producing the distinct proteins that can target cancerous cells. The drugs used were decitabine, which treats myelodysplastic syndromes, and panobinostat, used for multiple myeloma.
Before trialing this approach in humans, the researchers aim to refine the epigenetic treatments to specifically induce neoantigen production in tumor cells only. They noted in the study that while normal cells also generated targets when exposed to the two drugs, they produced them at lower levels than glioblastoma cells. Wang and Kim acknowledged the potential for unwanted side effects if normal cells also create these targets.
In their ongoing research, Wang and Kim are exploring how CRISPR gene editing could be employed to activate specific genome segments in cancer cells, allowing them to create the same neoantigens found across the human population. This strategy may enable a wide array of tumors, even those of different types, to share similar targets that could respond to the same immunotherapy, protecting healthy cells in the process. There are multiple avenues to attack such shared targets, including checkpoint inhibitors, vaccines, and engineered T-cells.
“Immunotherapy has dramatically changed the treatment landscape for certain cancers, like melanoma,” stated Kim, who practices at Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine and heads the Brain Tumor Center. “Advancements in glioblastoma treatment have been more gradual due to the tumor’s resilience against current therapies. However, with the latest developments in both immunotherapy and epigenetic treatments, I believe we are making significant strides towards transformative changes in glioblastoma care.”
