Drug combination blames brain tumor cells for attacks on the immune system

Even when treated with the most advanced therapies, patients with glioblastoma – an aggressive brain tumor – typically survive less than two years after diagnosis. Attempts to treat this cancer with the latest immunotherapies have been unsuccessful, likely because glioblastoma cells have few, if any, natural targets for the immune system.

In a cell-based study, scientists at Washington University School of Medicine in St. Louis forced glioblastoma cells to display immune system targets, potentially making them visible to immune cells and newly susceptible to immunotherapies. The strategy involves a combination of two drugs, each already approved by the FDA to treat different types of cancer.

The study is online in the journal Nature Genetics.

“For patients whose tumors do not naturally produce targets for immunotherapy, we have shown that there is a way to induce their production,” said co-senior author Ting Wang, PhD, Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine and Head of the Department of Genetics at WashU Medicine. “In other words, if there is no goal, we can create one. This is a completely new way to develop targeted and precise therapies for cancer. We are confident that in the near future we will be able to begin clinical trials combining immunotherapy with this strategy to provide new therapeutic approaches for patients with very difficult-to-treat cancers.”

To create immune targets on cancer cells, Wang focused on stretches of DNA in the genome known as transposable elements. According to Wang, transposable elements have become a double-edged sword in cancer in recent years. His work has shown that transposable elements play a role in tumorigenesis, although they have vulnerabilities that could be exploited to develop new cancer treatment strategies.

For this study, Wang’s team took advantage of the fact that transposable elements can naturally cause a tumor to produce random proteins that are unique to the tumor and not present in normal cells. These unusual proteins, called tumor antigens or neoantigens, could be targets for immunotherapies such as checkpoint inhibitors, antibodies, vaccines and genetically engineered T cell therapies.

Nevertheless, in some tumors, including glioblastomas, there are few immune targets that are naturally generated by transposable elements. To address this problem, Wang and his colleagues, including co-senior author Albert H. Kim, MD, PhD and August A. Busch Jr. Professor of Neurological Surgery, have shown how to specifically force transposable elements to target immune system targets Glioblastomas produce cells that normally lack them.

The researchers used a combination of two drugs that affect the so-called epigenome, which controls which genes in a cell are activated and to what extent. When treated with the two epigenetic therapy drugs, the tightly packed DNA molecules of the glioblastoma cells unfolded and released transposable elements that began producing unusual proteins that could be used to fight the cancer cells. The two drugs were decitabine, which is approved to treat myelodysplastic syndromes, a group of blood cancers; and panobinostat, which is approved for the treatment of multiple myeloma, a cancer of the white blood cells.

Before this strategy is examined in humans, the researchers are looking for ways to specifically use epigenetic therapy so that only the tumor cells are stimulated to produce neoantigens. In the new study, researchers warned that normal cells also produced targets when exposed to the two drugs. Although normal cells did not produce as many neoantigens as the glioblastoma cells, there is a risk of unwanted side effects if normal cells also produce these targets, according to Wang and Kim.

In their ongoing work, Wang and Kim are studying how to use the molecular editing technology CRISPR to make specific parts of the genome in cancer cells produce the same transposable element neoantigens that are common throughout the human population. Such a strategy could provide the same targets to the tumors of many patients—even different types of cancer—that could respond to the same immunotherapy while sparing healthy cells. There are then several possible ways to pursue such a common goal, including checkpoint inhibitors, vaccines, engineered antibodies and engineered T cells.

“Immunotherapy has revolutionized the treatment of some specific cancers, such as melanoma,” said Kim, who treats patients at the Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine and is also director of the Brain Tumor Center there. “Progress in glioblastoma has been comparatively slow because this tumor is resistant to the latest therapeutic strategies. But with recent advances in immunotherapies and epigenetic therapies that could be used in combination, I hope we are on the right track for a similar transformative change in the treatment of glioblastoma.”

Reference: Jang HJ, Shah NM, Maeng JH, et al. Epigenetic therapy enhances transcription of transposable elements to generate tumor-enriched antigens in glioblastoma cells. Nat Genet. 2024;56(9):1903-1913. doi:10.1038/s41588-024-01880-x

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