Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma
Year: 2022
Type: preprint
Abstract: Immune checkpoint blockers (ICBs) have failed in all Phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following anti-PD1 antibody treatment that disrupts the blood-tumor-barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a “hot” tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients. One-Sentence Summary Losartan prevents immunotherapy-associated edema and enhances the outcome of immunotherapy in glioblastoma.
Authors: Meenal Datta, Sampurna Chatterjee, Elizabeth M. Perez, Simon Gritsch, Sylvie Roberge, Mark Duquette, Ivy X. Chen, Kamila Naxerova, Ashwin S. Kumar, Mitrajit Ghosh, Kyrre E. Emblem, Mei R. Ng, William W. Ho, Pragya Kumar, Shanmugarajan Krishnan, Xinyue Dong, Maria C. Speranza, Martha R. Neagu, David A. Reardon, Arlene H. Sharpe, Gordon J. Freeman, Mario L. Suvà, Lei Xu, Rakesh K. Jain
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Defense, American Association for Cancer Research, European Commission, Agency for Science, Technology and Research, Deutsche Forschungsgemeinschaft, Norges Forskningsråd, National Institutes of Health, Loxo Oncology, Helse Sør-Øst RHF, National Cancer Institute
Awards: G1099328184, G1145426982, G4119534169, Understanding and Overcoming T cell Immunosuppression in Glioblastoma, G4259228269, Collaborative Research: Broadening Participation in Computing through Authentic, Collaborative Engagement with Computing for the Greater Good, G434337789, G5078342886, G5850682332, G7387888018, G8272788999, G8406153277, Reengineering obesity-induced abnormal microenvironment to improve PDAC treatment, G9000055905, G9000118450, G9000196310, G9000352085, Improving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolism
OpenAlex ID: W4283773429