Abnormal vascular structure and function within brain metastases is linked to pembrolizumab resistance
Albert E Kim, Kevin W Lou, Anita Giobbie-Hurder, Ken Chang, Mishka Gidwani, Katharina Hoebel, Jay B Patel, Mason C Cleveland, Praveer Singh, Christopher P Bridge, Syed Rakin Ahmed, Benjamin A Bearce, William Liu, Elies Fuster-Garcia, Eudocia Q Lee, Nancy U Lin, Beth Overmoyer, Patrick Y Wen, Lakshmi Nayak, Justine V Cohen, Jorg Dietrich, April Eichler, Rebecca Heist, Ian Krop, Donald Lawrence, Jennifer Ligibel, Sara Tolaney, Erica Mayer, Eric 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- Cancer Research
- Neurology (clinical)
- Oncology
Abstract
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 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 (VAI), 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 towards a decrease in under-perfused tissue, suggesting a reversal of the negative effects of hypoxia. In the peri-tumor region, development of smaller blood vessels, consistent with neo-angiogenesis, was associated with tumor growth before radiographic evidence of contrast enhancement on anatomical MRI.
Conclusions
This study, one of the largest functional imaging studies for BM, suggests that vascular architecture is linked with ICI efficacy. Studies identifying modulators of vascular architecture, and effects on immune activity, are warranted and may inform future combination treatments.