Enhanced brain entry of checkpoint-inhibitory therapeutic antibodies facilitated by intraarterial NEO100 in mouse models of brain-localized malignancies
| Autor: | Weijun Wang, Haiping He, Shan Zeng, Hee-Yeon Cho, Radu O. Minea, Steven D. Swenson, Long Zheng, Alan L. Epstein, Apostolos Stathopoulos, Ligang Chen, Axel H. Schönthal, Thomas C. Chen |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Journal of Neurosurgery. :1-9 |
| ISSN: | 1933-0693 0022-3085 |
| DOI: | 10.3171/2022.12.jns221285 |
| Popis: | OBJECTIVE Immune checkpoint-inhibitory therapeutic antibodies have shown striking activity against several types of cancers but are less effective against brain-localized malignancies, in part due to the protective effect of the blood-brain barrier (BBB). The authors hypothesized that intraarterial (IA) delivery of a novel compound, NEO100, has the potential to safely and reversibly open the BBB to enable brain-targeted therapeutic activity of checkpoint-inhibitory antibodies. METHODS Immunocompetent mice with syngeneic glioblastoma or melanoma cells implanted into their brains were subjected to a single IA injection of NEO100 to open their BBB. One dose of murine anti–PD-1/PD-L1 antibody was either coinjected with NEO100 or separately injected intravenously. Brain penetration of these antibodies and levels of CD8+ T cell infiltrate into the tumor microenvironment were quantitated and animal survival was monitored. RESULTS IA NEO100 enabled the increased accumulation of checkpoint-inhibitory antibodies in the brain, along with greater numbers of T cells. In both malignancy models, a single intervention of IA NEO100 combined with antibody resulted in the long-term survival of animals. Antibody treatment in the absence of NEO100 was far less effective. CONCLUSIONS BBB opening by IA NEO100 facilitates brain tumor access by checkpoint-inhibitory antibodies and enables their therapeutic activity, along with increased levels of T-cell recruitment. |
| Databáze: | OpenAIRE |
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