title: Dynamic contrast enhanced MRI detects early response to adoptive NK cellular immunotherapy targeting the NG2 proteoglycan in a rat model of glioblastoma.
abstract: 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.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway; Cardiovascular Research Group, Haukeland University Hospital, Bergen, Norway.
authors.forename: Cecilie Brekke
authors.initials: CB
authors.lastname: Rygh
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: MI Lab, Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway.
authors.forename: Marte
authors.initials: M
authors.lastname: Thuen
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gras Navarro
authors.affiliation: MI Lab, Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway.
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Huuse
authors.affiliation: Molecular Imaging Center, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Frits
authors.initials: F
authors.lastname: Thorsen
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway; Laboratoire d'Immunogénétique-Allergologie, CRP-Santé, Luxembourg City, Luxembourg.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Poli
authors.affiliation: Laboratoire d'Immunogénétique-Allergologie, CRP-Santé, Luxembourg City, Luxembourg.
authors.forename: Jacques
authors.initials: J
authors.lastname: Zimmer
authors.affiliation: MI Lab, Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway; Department of Medical Imaging, St. Olavs Hospital, Trondheim, Norway.
authors.forename: Olav
authors.initials: O
authors.lastname: Haraldseth
authors.affiliation: Institute for Clinical Dentistry, University of Bergen, Bergen, Norway.
authors.forename: Stein Atle
authors.initials: SA
authors.lastname: Lie
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.
authors.forename: Per Øyvind
authors.initials: PØ
authors.lastname: Enger
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway; Institute for Clinical Dentistry, University of Bergen, Bergen, Norway.
authors.forename: Martha
authors.initials: M
authors.lastname: Chekenya
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000941:Antigens / Q000235:genetics / Q000276:immunology; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004058:Diffusion; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D007089:Image Enhancement; D016219:Immunotherapy, Adoptive; D015552:Injections, Intralesional; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation*; D008279:Magnetic Resonance Imaging; D008297:Male; D058990:Molecular Targeted Therapy; D011509:Proteoglycans / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D051381:Rats; D011923:Rats, Nude; D047368:Tumor Burden / Q000187:drug effects; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4