Abstract
NEO100 is a GMP grade highly purified version of perillyl alcohol (POH), a monoterpene with cell cycle inhibitor properties. It is currently administered intranasally in Phase I/IIa IND trial in the United States for patients with recurrent GBM. Recently, we have found that NEO100 may be administered in a vitro setting, resulting in transient opening of the blood brain barrier. We have confirmed this finding in-vivo using an intracardiac injection of NEO100; intracardiac injection is used as an intra-arterial model for small rodents. Evans Blue injected intravenously after intracardiac NEO100 leads to staining throughout the whole brain. This effect is seen for up to 6 hours after injection; after that time, no Evans Blue stain is seen in the brain. We then injected a small molecule (dopamine), which normally does not cross the blood brain barrier. We were able to detect dopamine in the brain via HPLC after intracardiac injection of NEO100, followed by intravenous dopamine. Having demonstrated that non BBB permeable small molecules can cross into the brain with intra-arterial NEO100, we then tested fluorescent antibodies. Again, intracardiac injection of NEO100 followed by intravenous fluorescent antibodies allowed the antibodies to be detected in the normal brain. An in-vivo intracranial model of GL26 tumor was created. The checkpoint inhibitor antibody (anti-PD1) was used. Four groups (6 animals per group) were treated: Group 1-saline alone Group 2-NEO100 alone Group 3-anti-PD1 alone Group 4-NEO100 followed by anti-PD1. Kaplan Meier survival curves were constructed. All animals in Group 1 and Group 2 passed away within one week. Group 3 had one survivor, Group 4-all six animals survived and are still doing well. We will be translating this study into a clinical trial using interventional neuroradiology to deliver NEO100, followed by intravenous administration of anti-PD1.