Abstract 1471: Immunotherapy revised: Ipilimumab potentiates the vascular response to stereotactic radiosurgery in patients with brain metastases
Authors: Digernes Ingrid , Saxhaug Cathrine , Geier Oliver , Reitan Edmund , Waldeland Einar , Hole Kunt Håkon , Jacobsen Kari Dolven , Helland Åslaug , Emblem Kyrre Eeg 
Published: July 2016

Abstract
Introduction: While immunotherapy is a promising treatment option for advanced metastatic disease, the survival benefit of adding ipilimumab to stereotactic radiosurgery (SRS) in unselected patients with metastases to the brain seems limited [1, 2]. Moreover, because conventional diagnostic methods for assessing treatment response were not designed for these therapies, the mechanisms of action in vivo are poorly understood. To reveal potential synergistic effects of adding ipilimumab to SRS, we here present preliminary data on the vascular response to SRS and ipilimumab in patients with brain metastases from malignant melanomas and non-small cell lung cancer.
Methods: Voxel-wise estimations of blood volume and vessel calibers were acquired by perfusion MRI and Vessel Architectural Imaging [3], respectively, in 13 patients with brain metastases from lung cancer receiving SRS only (N = 6; 7 lesions) and malignant melanomas receiving SRS only (N = 4; 5 lesions) or SRS and ipilimumab (N = 3; 5 lesions). Regions of enhancing tumor were identified on contrast-enhanced MRIs, whereas peri-tumoral tissue regions included a region containing a 2mm wide dilation of the enhancing tumor and outside the SRS target area. MRIs were performed at baseline (pre SRS) and repeated every three months. Ipilimumab (3mg/kg) were administered intravenously over 90 min every third week for four cycles. SRS was delivered to the tumor (visual metastasis + 2 mm margin) with a peripheral dose of 18 Gy or 25 Gy, depending on tumor size.
Results: For patients treated with SRS only, the vessel calibers decreased with a median value of 15% in the peri-tumoral area at 3 months following SRS (P&lt;0.05, Wilcoxon signed rank test) and more in metastases from lung cancer than in melanomas (75% vs 95%, P&lt;0.05, Mann-Whitney U test). In contrast, for patients treated with SRS and ipilimumab, there was almost a two-fold increase in the average vessel caliber size in the peri-tumoral area at 3 months (P&lt;0.05 vs SRS only, Mann-Whitney U test). Non-significant trends towards lower blood volume values and tumor volumes were observed in all groups at 3 months.
Conclusion: The enlarged average vessel calibers and the subsequent lack of an increase in blood volume suggest ipilimumab helps clean up the vascular bed by removing small caliber vessels and effectively reducing the capillary vessel density. Our advanced MRI data provide valuable and novel insights into the biological mechanisms of response to ipilimumab and at study end may help identify patients with metastatic disease that benefit from this therapy by prolonged survival.
References:
1. Mathew et al, Melanoma Res 2013. 23(3):191-5
2. Patel et al, Am J Clin Oncol 2015. May 16:[Epub]
3. Emblem et al, Nat Med 2013. 19(9):1178-83
Citation Format: Ingrid Digernes, Cathrine Saxhaug, Oliver Geier, Edmund Reitan, Einar Waldeland, Kunt Håkon Hole, Kari Dolven Jacobsen, Åslaug Helland, Kyrre Eeg Emblem. Immunotherapy revised: Ipilimumab potentiates the vascular response to stereotactic radiosurgery in patients with brain metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1471.