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 been unsuccessful, likely 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 immune system targets, potentially making them visible to immune cells and newly vulnerable to immunotherapies. The strategy involves a combination of two drugs, each already FDA-approved to treat different cancers.
The study is online in the journal Nature Genetics.
“For patients whose tumors do not naturally produce targets for immunotherapy, we showed there is a way to induce their generation,” said co-senior author Ting Wang, PhD, the Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine and head 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 will be able to move into clinical trials, where immunotherapy can be combined with this strategy to provide new therapeutic approaches for patients with very hard-to-treat cancers.”
To create immune targets on cancer cells, Wang has focused on stretches of DNA in the genome known as transposable elements. In recent years, transposable elements have emerged as a double-edged sword in cancer, according to Wang. His work has shown that transposable elements play a role in causing tumors to develop even as 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 transposable elements naturally can cause a tumor to churn out random proteins that are unique to the tumor and not present in normal cells. Called tumor antigens or neoantigens, these unusual proteins could be the targets for immunotherapies, such as checkpoint inhibitors, antibodies, vaccines and genetically engineered T cell therapies.
Even so, some tumors, including glioblastoma, have few immune targets produced naturally by transposable elements. To address this, Wang and his colleagues, including co-senior author Albert H. Kim, MD, PhD, the August A. Busch Jr. Professor of Neurological Surgery, have demonstrated how to purposely force transposable elements to produce immune system targets on glioblastoma cells that normally lack them.