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.
The researchers used a combination of two drugs that influence the so-called epigenome, which controls which genes are turned on in a cell and to what degree. When treated with the two epigenetic therapy drugs, the tightly packed DNA molecules of the glioblastoma cells unfurled, triggering transposable elements to begin making the unusual proteins that could be used to target 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 multiple myeloma, a cancer of white blood cells.
Before investigating this strategy in people, the researchers are seeking ways to target the epigenetic therapy so that only the tumor cells are induced to make neoantigens. In the new study, the researchers cautioned that normal cells also produced targets when exposed to the two drugs. Even though normal cells didn't produce as many neoantigens as the glioblastoma cells did, Wang and Kim said there is a risk of unwanted side effects if normal cells create these targets as well.
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 give many patients' tumors — even different cancer types — the same targets that could respond to the same immunotherapy, while sparing healthy cells. There are then multiple possible ways to go after 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 the director of the Brain Tumor Center there. "Progress in glioblastoma has been slow by comparison because of how resistant this tumor is to the latest therapeutic strategies. But with recent advancements in immunotherapies and epigenetic therapies that could be used in combination, I'm hopeful that we are on the right path for a similar transformative change in the treatment of glioblastoma."
Jang HJ, Shah NM, Maeng JH, Liang Y, Basri NL, Ge J, Qu X, Mahlokozera T, Tzeng S, Williams RB, Moore MJ, Annamalai D, Chen JY, Lee HJ, DeSouza PA, Li D, Xing X, Kim AH, Wang T. Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells. Nature Genetics. Sept. 2, 2024.
This work was supported by the National Institutes of Health (NIH), grant numbers 5R01HG007175, U24ES026699, U01HG009391, T32GM007067, P30DK020579, UL1TR002345 and P30CA091842; the American Cancer Society Research Scholar Grant, number RSG-14-049-01-DMC; the Howard Hughes Medical Institute; and the National Science Foundation, grant number DBI-1827534. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
About Washington University School of Medicine
WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,900 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 56% in the last seven years. Together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,900 faculty physicians practicing at 130 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children's hospitals of BJC HealthCare . WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.
