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

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 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 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.

• Authors: 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
• Journal: Neuro-oncology (Neuro Oncol) Vol. 26 Issue 5 Pg. 965-974 (May 03 2024) ISSN: 1523-5866 [Electronic] England
• PMID: 38070147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Clinical Trial, Phase II)
• Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].

Chemical References

• pembrolizumab
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• Immune Checkpoint Inhibitors

Topics

• Humans
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Brain Neoplasms (drug therapy, secondary, diagnostic imaging)
• Female
• Drug Resistance, Neoplasm
• Male
• Middle Aged
• Aged
• Antineoplastic Agents, Immunological (therapeutic use)
• Magnetic Resonance Imaging
• Adult
• Prognosis
• Immune Checkpoint Inhibitors (therapeutic use)
• Neovascularization, Pathologic (drug therapy, pathology)
• Follow-Up Studies