Researchers revealed that the blood pressure drug losartan may prevent immunotherapy-induced edema and allow patients with glioblastoma to continue receiving immune checkpoint inhibitors without developing adverse effects in the brain, according to a new study published by Datta et al in Proceedings of the National Academy of Sciences (PNAS).
Background
Patients with glioblastoma have been known to benefit from immune checkpoint inhibitors that stimulate an immune response against cancer cells; however, they may also experience cerebral edema during treatment.
In these patients, cerebral edema is currently controlled by steroids that are highly immunosuppressive and counter the benefits of immunotherapy. Thus, new drugs that safely control cerebral edema without causing immunosuppression are urgently needed.
Study Methods and Results
Through the use of mouse models of cancer, single-cell RNA sequencing, immune cell blocking studies, and analyses of patient imaging scans, researchers demonstrated that immunotherapy-induced cerebral edema may result from an inflammatory response that disrupts the blood-tumor barrier. This response involves the enzymes matrix metalloproteinases 14 and 15—which reside in cells lining tumor-associated blood vessels and induce blood vessel leakage to cause cerebral edema.
The new study revealed that losartan can prevent immunotherapy-related cerebral edema by reducing the expression of these enzymes. Combined with an immune checkpoint inhibitor, losartan improved survival in mouse models of glioblastoma—curing 20% of mice, and 40% when combined with chemoradiation followed by surgery.
Conclusions
“Cerebral edema is in and of itself a hallmark of primary brain tumors such as glioblastoma. In patients [with this disease], we found that immune checkpoint [inhibitors], on average, increase cerebral edema by approximately 20%. This is not only neurologically detrimental to patients, it can even be lethal,” explained senior study author Rakesh K. Jain, PhD, the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School and Director of the Edwin L. Steele Laboratories for Tumor Biology at Massachusetts General Hospital.
“Most patients who experience [cerebral] edema receive steroids to reduce the brain swelling; however, these drugs … [can] counteract the effects of immunotherapy. Therefore, we have identified a viable pharmaceutical option for [cerebral] edema control that addresses the underlying mechanism of immunotherapy-induced edema and also sensitizes the tumor microenvironment to immune checkpoint [inhibitor] therapy,” he added.
The researchers emphasized that because losartan may be safe, effective, and affordable, it can be readily prescribed along with immunotherapy to patients with glioblastoma.
Building on a previous study published by Chen et al in PNAS to identify biomarkers of response to immunotherapy, the researchers also identified factors in the tumor microenvironment that may predict which patients are most likely to benefit from such a combination. They concluded that their findings of a potential for enhanced antitumor immune responses when pairing losartan with immune checkpoint inhibitors further supported the need for additional studies evaluating the full benefits of this treatment option for patients with glioblastoma.
Disclosure: The research in this study was supported by grants from the National Cancer Institute, National Foundation for Cancer Research, Nile Albright Research Foundation, Jane’s Trust Foundation, and Ludwig Cancer Center at Harvard. For full disclosures of the study authors, visit pnas.org.
