Abnormal vascular structure and function within brain metastases is linked to pembrolizumab resistance

作者：Albert E. Kim, Kevin W Lou, Anita Giobbie‐Hurder, Ken Chang, Mishka Gidwani, Katharina Hoebel, Jay Patel, Mason C. Cleveland, Praveer Singh, Christopher P. Bridge, Syed Rakin Ahmed, Benjamin Bearce, William J. Liu, Elies Fuster‐García, Eudocia Q. Lee, Nancy U. Lin, Beth Overmoyer, Patrick Y. Wen, Lakshmi Nayak, Justine V. Cohen, Jörg Dietrich, April F. Eichler, Rebecca S. Heist, Ian E. Krop, Donald P. Lawrence, Jennifer A. Ligibel, Sara M. Tolaney, Erica L. Mayer, Eric P. Winer, Carmen M. Perrino, Elizabeth J Summers, Maura Mahar, Kevin Oh, Helen A. Shih, Daniel P. Cahill, Bruce R. Rosen, Yi‐Fen Yen, Jayashree Kalpathy–Cramer, Maria Martinez‐Lage, Ryan J. Sullivan, Priscilla K. Brastianos, Kyrre E. Emblem, Elizabeth R. Gerstner · 发表于：Neuro-Oncology · 年份：2023 · DOI：10.1093/neuonc/noad236 · 被引用次数：6 · 研究领域：Brain Metastases and Treatment、Glioma Diagnosis and Treatment、Cancer Immunotherapy and Biomarkers

BACKGROUND: We recently conducted a phase 2 trial (NCT028865685) evaluating intracranial efficacy of pembrolizumab for brain metastases (BM) of diverse histologies. Our study met its primary efficacy endpoint and illustrates that pembrolizumab exerts promising activity in a select group of patients with BM. Given the importance of aberrant vasculature in mediating immunosuppression, we explored the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture in the hopes of identifying potential mechanisms of intracranial ICI response or resistance for BM. METHODS: Using Vessel Architectural Imaging, a histologically validated quantitative metric for in vivo tumor vascular physiology, we analyzed dual-echo DSC/DCE MRI for 44 patients on trial. Tumor and peri-tumor cerebral blood volume/flow, vessel size, arterial and venous dominance, and vascular permeability were measured before and after treatment with pembrolizumab. RESULTS: BM that progressed on ICI were characterized by a highly aberrant vasculature dominated by large-caliber vessels. In contrast, ICI-responsive BM possessed a more structurally balanced vasculature consisting of both small and large vessels, and there was a trend toward a decrease in under-perfused tissue, suggesting a reversal of the negative effects of hypoxia. In the peri-tumor region, the development of smaller blood vessels, consistent with neo-angiogenesis, was associated with tumor growth before radiographic evidence ...