Even treated with the most advanced therapies, patients with glioblastoma (an aggressive brain cancer) typically survive less than two years after diagnosis. Efforts to treat this cancer with the latest immunotherapies have not been successful, probably because glioblastoma cells have few, if any, natural targets for the immune system to attack.
In a cell-based study, scientists at Washington University School of Medicine in St. Louis have forced glioblastoma cells to display targets in the immune system, making them potentially visible to immune cells and newly vulnerable to immunotherapies. . The strategy involves a combination of two drugs, each of which is 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 show that there is a way to induce their generation,” said co-senior author Ting Wang, PhD, Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine and chair of the Department. of Genetics at WashU Medicine. “In other words, when there is no target, we can create one. This is a very new way of designing targeted and precision therapies for cancer. We are hopeful that in the near future we can move to clinical trials, where immunotherapy can be combined with this strategy to provide new therapeutic approaches for patients with very difficult-to-treat cancers.”
To create immune targets in cancer cells, Wang has focused on stretches of DNA in the genome known as transposable elements. In recent years, transposable elements have become a double-edged sword in cancer, according to Wang. Their work has shown that transposable elements play a role in tumor development even when they present vulnerabilities that could be exploited to create new cancer treatment strategies.
For this study, Wang’s team took advantage of the fact that naturally transposable elements can cause a tumor to produce random proteins that are unique to the tumor and are 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 modified T cell therapies.
Still, some tumors, including glioblastoma, have few immunological targets naturally produced by transposable elements. To address this, Wang and his colleagues, including co-senior author Albert H. Kim, MD, PhD, August A. Busch Jr. Professor of Neurological Surgery, have shown how to intentionally force transposable elements to produce immune system targets in glioblastoma. cells that normally lack them.
The researchers used a combination of two drugs that influence the so-called epigenome, which controls which genes are activated in a cell and to what degree. When treated with the two epigenetic therapy drugs, the glioblastoma cells’ tightly packed DNA molecules unfolded, causing transposable elements to begin producing unusual proteins that could be used to attack the cancer cells. The two drugs were decitabine, approved to treat myelodysplastic syndromes, a group of blood cancers; and panobinostat, which is approved for multiple myeloma, a cancer of the white blood cells.
Before investigating this strategy in people, researchers are looking for ways to target epigenetic therapy so that only tumor cells are induced to produce neoantigens. In the new study, the researchers noted that normal cells also produced targets when exposed to the two drugs. Although normal cells did not produce as many neoantigens as glioblastoma cells, Wang and Kim said there is a risk of unwanted side effects if normal cells also create these targets.
In ongoing work, Wang and Kim are investigating how to use CRISPR molecular editing technology to induce specific parts of the genome in cancer cells to produce the same neoantigens from transposable elements that are common across the human population. Such a strategy could provide many patients’ tumors (even different types of cancer) with the same targets that could respond to the same immunotherapy, while preserving healthy cells. So there are multiple possible ways to pursue such a shared target, 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 Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, and is also director of the Brain Tumor Center. from that place. “By comparison, progress in glioblastoma has been slow because of how resistant this tumor is to the latest therapeutic strategies. But with recent advances in immunotherapies and epigenetic therapies that could be used in combination, I am hopeful that we are at the right path for a similar transformative change in glioblastoma treatment.