Pre-operative stereotactic radiosurgery and peri-operative dexamethasone for resectable brain metastases: a two-arm pilot study evaluating clinical outcomes and immunological correlates

Caroline S. Jansen, Meghana S. Pagadala, Maria A. Cardenas, Roshan S. Prabhu, Subir Goyal, Chengjing Zhou, Prasanthi Chappa, BaoHan T. Vo, Chengyu Ye, Benjamin Hopkins, Jim Zhong, Adam Klie, Taylor Daniels, Maedot Admassu, India Green, Neil T. Pfister, Stewart G. Neill, Jeffrey M. Switchenko, Nataliya Prokhnevska, Kimberly B. Hoang, Mylin A. Torres, Suzanna Logan, Jeffrey J. Olson, Edjah K. Nduom, Luke Balzo, Kirtesh Patel, Stuart H. Burri, Anthony L. Asher, Scott Wilkinson, Ross Lake, Aparna H. Kesarwala, Kristin A. Higgins, Pretesh Patel, Vishal Dhere, Adam G. Sowalsky, Hannah Carter, Mohammad K. Khan, Haydn Kissick () and Zachary S. Buchwald ()
Additional contact information
Caroline S. Jansen: Emory University
Meghana S. Pagadala: Memorial Sloan Kettering Cancer Center
Maria A. Cardenas: Emory University
Roshan S. Prabhu: Atrium Health
Subir Goyal: Emory University
Chengjing Zhou: Emory University
Prasanthi Chappa: Emory University
BaoHan T. Vo: Emory University
Chengyu Ye: Emory University
Benjamin Hopkins: Emory University
Jim Zhong: Emory University
Adam Klie: University of California San Diego
Taylor Daniels: Emory University
Maedot Admassu: Emory University
India Green: Emory University
Neil T. Pfister: University of Alabama Birmingham
Stewart G. Neill: Emory University
Jeffrey M. Switchenko: Emory University
Nataliya Prokhnevska: Emory University
Kimberly B. Hoang: Emory University
Mylin A. Torres: Emory University
Suzanna Logan: Nationwide Children’s Hospital
Jeffrey J. Olson: Emory University
Edjah K. Nduom: Emory University
Luke Balzo: Emory University
Kirtesh Patel: Kaiser Permanente
Stuart H. Burri: Atrium Health
Anthony L. Asher: Atrium Health
Scott Wilkinson: National Cancer Institute
Ross Lake: National Cancer Institute
Aparna H. Kesarwala: Emory University
Kristin A. Higgins: Emory University
Pretesh Patel: Emory University
Vishal Dhere: Emory University
Adam G. Sowalsky: National Cancer Institute
Hannah Carter: University of California San Diego
Mohammad K. Khan: Emory University
Haydn Kissick: Emory University
Zachary S. Buchwald: Emory University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

Date: 2024
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DOI: 10.1038/s41467-024-53034-6

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