| Autor: |
Rygh CB; Department of Biomedicine, University of Bergen, Bergen, Norway; Cardiovascular Research Group, Haukeland University Hospital, Bergen, Norway., Wang J; Department of Biomedicine, University of Bergen, Bergen, Norway., Thuen M; MI Lab, Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway., Gras Navarro A; Department of Biomedicine, University of Bergen, Bergen, Norway., Huuse EM; MI Lab, Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway., Thorsen F; Molecular Imaging Center, Department of Biomedicine, University of Bergen, Bergen, Norway., Poli A; Department of Biomedicine, University of Bergen, Bergen, Norway; Laboratoire d'Immunogénétique-Allergologie, CRP-Santé, Luxembourg City, Luxembourg., Zimmer J; Laboratoire d'Immunogénétique-Allergologie, CRP-Santé, Luxembourg City, Luxembourg., Haraldseth O; MI Lab, Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway; Department of Medical Imaging, St. Olavs Hospital, Trondheim, Norway., Lie SA; Institute for Clinical Dentistry, University of Bergen, Bergen, Norway., Enger PØ; Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway., Chekenya M; Department of Biomedicine, University of Bergen, Bergen, Norway; Institute for Clinical Dentistry, University of Bergen, Bergen, Norway. |
| Abstrakt: |
There are currently no established radiological parameters that predict response to immunotherapy. We hypothesised that multiparametric, longitudinal magnetic resonance imaging (MRI) of physiological parameters and pharmacokinetic models might detect early biological responses to immunotherapy for glioblastoma targeting NG2/CSPG4 with mAb9.2.27 combined with natural killer (NK) cells. Contrast enhanced conventional T1-weighted MRI at 7±1 and 17±2 days post-treatment failed to detect differences in tumour size between the treatment groups, whereas, follow-up scans at 3 months demonstrated diminished signal intensity and tumour volume in the surviving NK+mAb9.2.27 treated animals. Notably, interstitial volume fraction (ve), was significantly increased in the NK+mAb9.2.27 combination therapy group compared mAb9.2.27 and NK cell monotherapy groups (p = 0.002 and p = 0.017 respectively) in cohort 1 animals treated with 1 million NK cells. ve was reproducibly increased in the combination NK+mAb9.2.27 compared to NK cell monotherapy in cohort 2 treated with increased dose of 2 million NK cells (p<0.0001), indicating greater cell death induced by NK+mAb9.2.27 treatment. The interstitial volume fraction in the NK monotherapy group was significantly reduced compared to mAb9.2.27 monotherapy (p<0.0001) and untreated controls (p = 0.014) in the cohort 2 animals. NK cells in monotherapy were unable to kill the U87MG cells that highly expressed class I human leucocyte antigens, and diminished stress ligands for activating receptors. A significant association between apparent diffusion coefficient (ADC) of water and ve in combination NK+mAb9.2.27 and NK monotherapy treated tumours was evident, where increased ADC corresponded to reduced ve in both cases. Collectively, these data support histological measures at end-stage demonstrating diminished tumour cell proliferation and pronounced apoptosis in the NK+mAb9.2.27 treated tumours compared to the other groups. In conclusion, ve was the most reliable radiological parameter for detecting response to intralesional NK cellular therapy. |
