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

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.

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Publication Details

Journal
Nature Communications
Published
2024-10-14
DOI
https://doi.org/10.1038/s41467-024-53034-6
Citations
9
Primary Topic
Brain Metastases and Treatment
Type
article
Field-Weighted Citation Impact
3.77

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article

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

Mylin A. Torres, Scott Wilkinson, Zachary S. Buchwald, Benjamin Hopkins et al.
9 citations
Nature Communications
Brain Metastases and Treatment
3.77
article

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

Mylin A. Torres, Scott Wilkinson, Zachary S. Buchwald, Benjamin Hopkins, Maria A. Cardenas, Caroline S. Jansen, Meghana S. Pagadala, Vishal R. Dhere, BaoHan T. Vo, Adam Klie, Adam G. Sowalsky, Stewart G. Neill, Neil T. Pfister, Ross Lake, Kimberly Bojanowski Hoang, Jeffrey M. Switchenko, Suzanna Logan, Luke del Balzo, Pretesh Patel, Subir Goyal, Chengyu Ye, Roshan S. Prabhu, Jeffrey J. Olson, Chengjing Zhou, Haydn Kissick, Nataliya Prokhnevska, India Green, Aparna H. Kesarwala, Kristin Ann Higgins, Edjah K. Nduom, Jim Zhong, Prasanthi Chappa, Mohammad K. Khan, Hannah Carter, Anthony L. Asher, T. C. Daniels, Stuart H. Burri, Kirtesh R. Patel, Maedot Admassu
article en
9 citations

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.

Nature CommunicationsVol. 15(1)
Nationwide Children's Hospital (US), Emory Healthcare (US), Memorial Sloan Kettering Cancer Center (US), Kaiser Permanente (US), Emory University (US), University of Alabama at Birmingham (US), University of California San Diego (US), Levine Cancer Institute (US), University of California San Diego Medical Center (US), National Cancer Institute (US), Southeast Radiation Oncology Group (US)
U.S. Department of Defense, American Cancer Society, Cancer Research Institute, Emory University, National Institutes of Health, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 6%
Brain Metastases and Treatment
3.77
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