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 intraarterial 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/ml 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 cm 3 (estimated from the volumetric MRI) without catastrophic embolicischemic 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.

Identification of neoepitopes recognized by tumor-infiltrating lymphocytes (TILs) from patients with glioma

“…Thus, a mutational analysis of the tumor following chemotherapy may uncover neoepitopes, which could elicit T-cell reactivity and be used for adjunct immunotherapy. The delivery of tumor-reactive T cells could either be systemic, or intra-cranial, as reported using chimeric antigen receptor (CAR) transgenic T cells to patients with GBM [ 34 , 35 ], the same route of delivery maybe considered for neoepitope-specific T cells after surgery [ 36 ].…”

Strategies for Improved Intra-arterial Treatments Targeting Brain Tumors: a Systematic Review

“…In addition, MRI may help to avoid adverse ischemic events in the clinical treatment of glioblastoma multiforme by intra-arterial infusion of tumor-infiltrating lymphocytes. This notion is supported by preclinical data showing that MRI is well-suited to evaluate ischemic events during intra-arterial infusion of activated T cells into the native rabbit brain ( 226 ).…”

A Primeval Mechanism of Tolerance to Desiccation Based on Glycolic Acid Saves Neurons from Ischemia in Mammals by Reducing Intracellular Calcium-Mediated Excitotoxicity

“…These results need to be further investigated as our study has certain limitations, such as: i) all experiments were done on young male mice, so the effect on different sex and/or age still needs to be tested, ii) mouse strains (C57BL/6N vs C57BL/6J), ischemia duration, time-points for analysis and treatment administration routes differed between the two in vivo models and therefore this can create a discrepancy in their sensitivity, iii) while both models mimic the mechanical thrombectomy occurring in the clinical setting, none of them mimics the pharmacological thrombolysis which is clinically achieved using recombinant tissue plasminogen activator (rTPA) and possible interactions between GA and rTPA should be ruled out. If confirmed in other animal models of media infarct in which the intra-arterial administration of the substances together with rtPA is possible [77] [78], this would have important implications in the clinical setting as it would be highly applicable in human stroke patients, where GA could be added during the reperfusion therapy acutely after stroke.…”

“…create a discrepancy in their sensitivity, iii) while both models mimic the mechanical thrombectomy occurring in the clinical setting, none of them mimics the pharmacological thrombolysis which is clinically achieved using recombinant tissue plasminogen activator(rTPA) and possible interactions between GA and rTPA should be ruled out. If confirmed in other animal models of media infarct in which the intra-arterial administration of the substances together with rtPA is possible[77] [78], this would have important implications in the clinical setting as it would be highly applicable in human stroke patients, where GA could be added during the reperfusion therapy acutely after stroke.AUTHOR CONTRIBUTIONSFP-M designed and coordinated the study. FP-M, IR-A and CF-S designed the OGD experiments.…”