The fast-growing and aggressive brain tumor known as glioblastoma has so far resisted all therapies, including immunotherapy, a treatment that harnesses the body’s immune system to destroy cancer cells.
In a new study, researchers have demonstrated how a safe and widely prescribed blood pressure drug increases the effectiveness of immunotherapy in mice with glioblastoma — curing 20% of mice when used alone and 40% when combined with chemoradiation and surgery.
The study, led by Meenal Datta, assistant professor of aerospace and mechanical engineering at the University of Notre Dame, was published in the Proceedings of the National Academy of Sciences (PNAS).
Some glioblastoma patients receiving immunotherapy experience increased brain swelling, or edema, which can be neurologically damaging or even life-threatening.
“Typically, patients with edema are given steroids to reduce inflammation, but that lowers the efficacy of the immunotherapy treatment,” said Datta. “The blood pressure medication losartan can reduce the edema as well as make immunotherapy more effective.”
Keeping blood vessels open in and around a tumor is critical to bringing in cancer-fighting drugs and immune cells and getting rid of unwanted fluids. Yet tumor blood vessels are poorly formed and leaky. In glioblastoma patients, Datta said, immunotherapy compounds this problem by triggering an uptick in enzymes that further impair the tumor blood vessel structure, increasing fluid buildup in the brain.
“Losartan not only reduces immunotherapy-induced edema, it improves the structure and function of tumor blood vessels and enhances the function of tumor-fighting immune cells,” said Datta.
The drug has already been tested clinically on other cancers and has been found to be effective in improving pancreatic cancer therapies. This new study shows that losartan can penetrate the blood-brain-barrier to reach glioblastoma and potentially other central nervous system tumors as well.
Datta joined the Notre Dame faculty in fall 2021. She directs the TIME Lab, which applies engineering concepts to incurable cancers to improve therapies. Her research focuses on immunomechanics, a new research subfield that explores the behavior of immune cells in the mechanically abnormal tumor microenvironment. She teaches in the Notre Dame Bioengineering program, the Materials Science and Engineering doctoral program, and in Aerospace and Mechanical Engineering.
This new research, carried out at Massachusetts General Hospital and Harvard Medical School with co-corresponding authors Mario L. Suva, Lei Xu, and Rakesh K. Jain, will serve as a foundation for future clinical studies.
— Karla Cruise, Notre Dame Engineering