Vessel Size Index MRI for Evaluating the Effects of Multiple Anti-Angiogenic Therapies in Sequence

Introduction. In vivo imaging of tumors treated with anti-angiogenic agents can reveal information about the therapeutic effects on tumor vasculature beyond simple tumor volume measurements. Vessel size index (VSI) MRI determines the fractional blood volume, mean vessel size, and Q (a dimensionless parameter related to vessel density) on a voxel-by-voxel basis, using changes in T2 and T2* caused by the injection of an iron oxide contrast agent [1,2]. In this study, we use VSI MRI to examine the effects of two potential therapies in sequence: B20-4.1, an antibody to vascular endothelial growth factor (anti-VEGF) [3], and anti-neuropilin (anti-NRP1), an anti-angiogenic agent which is believed to inhibit vessel maturation [4]. To account for tumor heterogeneity, we use viable tumor segmentation, restricting the VSI parameter analysis to the viable tumor tissue as determined by multispectral k-means clustering [5]. This technique has been previously shown to correlate well with ex vivo micro-CT angiography and histology [6]. In this study, the viable tumor VSI technique detected effects on the vasculature that showed a significant advantage to dosing with anti-NRP1 before anti-VEGF, rather than vice versa; this may indicate that anti-NRP1 treatment leaves vessels in an immature, VEGF-dependent state which then responds strongly to anti-VEGF treatment.