title: Safety of Intra-Arterial Injection With Tumor-Activated T Cells to the Rabbit Brain Evaluated by MRI and SPECT/CT.
abstract: Glioblastoma multiforme (GBM) is the most common and most severe form of malignant gliomas. The prognosis is poor with current combinations of pharmaceutical, radiotherapy, and surgical therapy. A continuous search for new treatments has therefore been ongoing for many years. Therapy with tumor-infiltrating lymphocytes (TILs) is a clinically promising strategy to treat various cancers, including GBM. An endovascular intra-arterial injection of TILs as a method of delivery may, instead of intravenous infusion, result in better retention of effector cells within the tumor. Prior to clinical trials of intra-arterial injections with any cells, preclinical safety data with special emphasis on embolic-ischemic events are necessary to obtain. We used native rabbits as a model for intra-arterial injections with routine clinical catheter material and a clinical angiography suite. We selectively infused a total dose of 20 million activated T cells at a cell concentration of 4,000 cells/μl over 8 min of injection time. The rabbits were evaluated for ischemic lesions by 9.4 T magnetic resonance imaging (MRI) (n = 6), and for tracking of injected cells, single-photon emission computed tomography/computed tomography (SPECT/CT) was used (n = 2). In this study, we show that we can selectively infuse activated T cells to a CNS volume of 3.5 cm3 (estimated from the volumetric MRI) without catastrophic embolic-ischemic adverse events. We had one adverse event with a limited basal ganglia infarction, probably due to catheter-induced mechanical occlusion of one of the lateral lenticulostriatal arteries. The cells pass through the native brain without leaving SPECT signals. The cells then, over the first hours, end up in the liver to a large extent and to a lesser degree by the spleen, pancreas, and kidneys. Virtually no uptake could be detected in the lungs. This indicates a difference in biodistribution as opposed to other cell types when infused intravenously.
authors.forename: Johan
authors.initials: J
authors.lastname: Lundberg
authors.forename: Emma
authors.initials: E
authors.lastname: Jussing
authors.forename: Zhenjiang
authors.initials: Z
authors.lastname: Liu
authors.forename: Qingda
authors.initials: Q
authors.lastname: Meng
authors.forename: Martin
authors.initials: M
authors.lastname: Rao
authors.forename: Erik
authors.initials: E
authors.lastname: Samén
authors.forename: Rikard
authors.initials: R
authors.lastname: Grankvist
authors.forename: Peter
authors.initials: P
authors.lastname: Damberg
authors.forename: Ernest
authors.initials: E
authors.lastname: Dodoo
authors.forename: Markus
authors.initials: M
authors.lastname: Maeurer
authors.forename: Staffan
authors.initials: S
authors.lastname: Holmin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D007269:Injections, Intra-Arterial / Q000009:adverse effects* / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D011817:Rabbits; D013601:T-Lymphocytes / Q000502:physiology*; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014057:Tomography, X-Ray Computed / Q000379:methods*