Enhancing brain entry and therapeutic activity of chimeric antigen receptor T cells with intra-arterial NEO100 in a mouse model of CNS lymphoma

作者：Weijun Wang, Haiping He, Long Zheng, Shan Zeng, Hee‐Yeon Cho, Aida Kouhi, Leslie A. Khawli, Ligang Chen, Apostolos Stathopoulos, Axel H. Schönthal, Alan L. Epstein, Thomas C. Chen · 发表于：Journal of neurosurgery · 年份：2023 · DOI：10.3171/2023.10.jns231097 · 被引用次数：5 · 研究领域：CAR-T cell therapy research、CNS Lymphoma Diagnosis and Treatment、Cutaneous lymphoproliferative disorders research

OBJECTIVE: Malignancies of the CNS are difficult to treat because the blood-brain barrier (BBB) prevents most therapeutics from reaching the intracranial lesions at sufficiently high concentrations. This also applies to chimeric antigen receptor (CAR) T cells, for which systemic delivery is inferior to direct intratumoral or intraventricular injection of the cells. The authors previously reported on a novel approach to safely and reversibly open the BBB of mice by applying intra-arterial (IA) injections of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol. The authors hypothesized that this method would enable enhanced brain entry and therapeutic activity of intravenously delivered CAR T cells, which the authors tested in a mouse model of CNS lymphoma. METHODS: Human Raji lymphoma cells were implanted into the brains of immune-deficient mice. After tumor uptake was confirmed with bioluminescent imaging, 0.3% NEO100 was injected intra-arterially, which was followed by intravenous (IV) delivery of CD19-targeted CAR T cells. After this single intervention, tumor growth was monitored with imaging, long-term survival of mice was recorded, and select mice were euthanized to analyze the distribution of CAR T cells in brain tissue. RESULTS: Intravenously injected CAR T cells could be readily detected in brain tumor areas after IA injection of NEO100 but not after IA injection of the vehicle (without NEO100). Although all untreated control animals died...