Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models
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 Rosa Ng, William W. Ho, Pragya Kumar, Shanmugarajan Krishnan, Xinyue Dong, Maria C. Speranza, Martha R. Neagu, J. Bryan Iorgulescu, Raymond Y. Huang, Gilbert Youssef, David A. Reardon, Arlene H. Sharpe, Gordon J. Freeman, Mario L. Suvà, Lei Xu, Rakesh K. Jain
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 CD8 + T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (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.