Essential oils for blood-brain barrier disruption: Preclinical studies of NEO100 in breast cancer brain metastases

See the article by Wang and He et al. pp 1656–1667

NEO100 is a purified form of perillyl alcohol. It is a plant-derived monoterpene composed of hydrophobic and hydrophilic regions. These essential oils which lend many plants their distinct smells and flavors have long been used in the treatment of infections, neurodegenerative and rheumatologic disorders, and cancers (both for supportive and therapeutic purposes). Within the context of central nervous system (CNS) tumors, perillyl alcohol has been under investigation for many years as a potential treatment for gliomas.^1,2 Wang et al previously presented their preclinical investigations of NEO100 use as an agent for transient diffuse blood-brain barrier (BBB) disruption to facilitate the administration of systemic therapies for the treatment of CNS malignancies.³

NEO100 when administered intra-arterially has been shown to disrupt the BBB, in both in vitro and in vivo models, at the tight junctions between endothelial cells. In the murine models, the effect is dose-dependent, immediate in onset, and appears to resolve within 4 hours. These findings are not recapitulated with intravenous administration nor with intra-arterial mannitol administration, indicating that both the route of administration and the specific agent used matter. The BBB disrupting activity of intra-arterial NEO100 when delivered in conjunction with intravenously administered systemic therapies is able to foster higher concentrations of those agents in the brains of the animal models. Specific systemic agents investigated included methotrexate, a PD-1 antibody, and chimeric antigen receptor T cells.³ This broad spectrum including cytotoxic anti-metabolites, antibodies, and cell therapies portends the potential value of exploring this platform across a wide range of therapeutic scenarios.

The current preclinical study by Wang and He et al investigates the role of this approach for the treatment of brain metastases from HER2+ breast cancer with trastuzumab or ado trastuzumab-emtansine (T-DM1).⁴ In a murine model, the team was able to demonstrate that intracardiac, a proxy for intra-arterial administration, of NEO100 was associated with the presence of intracranial trastuzumab after intravenous administration of the drugs with a preferential accumulation of the drug in tumor in comparison to surrounding brain. This was associated with improved survival compared to appropriate controls with a trend in favor of T-DM1 (although the studies were not designed to demonstrate the superiority of one agent over another). Of greater interest may be the increased intracranial immune infiltrate (investigated only in the trastuzumab-focused studies) consisting of natural killer cells, macrophages, and T cells suggesting a potential immunotherapeutic benefit.

Potential limitations regarding the translatability of the approach requires contemplation as next steps and future directions are considered. A single dose of HER2 targeted therapy with intra-arterial NEO100, as reported in the current study, would have a very low likelihood of improving median overall survival in a clinical trial of breast cancer brain metastases patients, most of whom die of systemic progression of disease. Radiographic improvement alone may not be a clinically meaningful endpoint. For extra-CNS disease, trastuzumab is typically administered on a weekly basis for metastatic breast cancer. Accompanying this with an intra-arterial procedure for NEO100 may not be practical due to patient risk and overall cost. The every 3-week dosing schedule of T-DM1 may be more feasible, but even that frequency of intra-arterial procedures would prove cumbersome. In turn, preclinical studies of various dosing schedules would be of importance. Potential advantages of this approach are the wide scope of companion therapeutics (cytotoxics, targeted therapies, immunotherapies, cell therapies, etc.) and disease states (primary and metastatic CNS tumors across a range of histologic and molecular subtypes) for which this platform could be applicable as well as the potential for decreased systemic doses of therapeutic to limit non-CNS toxicities.

The field of BBB disruption has been a fertile area of investigation for the treatment of brain tumors.⁵ A number of different approaches have been evaluated and at this time no single approach has proven superior to others. One approach, utilized in the preclinical studies by Wang and He et al, is the intra-arterial administration of an agent to directly disrupt the BBB. The most extensively studied agent is the hyperosmotic mannitol.⁶ The work by Wang and He et al demonstrated preclinical superiority of NEO100 when compared to mannitol in this regard. An alternative approach involves the use of a device to disrupt the BBB. An example undergoing extensive investigation is the employment of focused ultrasound for transient disruption.^7,8 Recent work in both of these realms and the current work with NEO100^3,4 reveals that BBB disruption in addition to serving as a means for cytotoxic agents to adequately penetrate the CNS also is associated with a local inflammatory response. A mechanistic understanding of what is driving this process is not yet fully understood. It does, however, begin to provide a framework for devising rational next steps for preclinical and clinical investigation for the treatment of CNS tumors.

Funding

R.V.L. is supported by NIH P50CA221747 and Brain Up 2137.

Conflict of interest statement

R.V.L. serves on the Novocure speakers’ bureau and has received honoraria from American Physician Institute Board Review CME, EBSCO publishing medical editing, MedLink Neurology medical editing, and Neurodiem presentation as well as research support (drug only) from BMS.