Key Points
- The 26th Annual Blood-Brain Barrier Consortium Meeting was held virtually on March 11 and 12.
- The meeting included presentations and posters on immunotherapy and drug delivery across the blood-brain barrier and blood-spinal cord barrier.
- Scott Burks, PhD, a staff scientist at the NIH Clinical Center, provided this report.
On March 11 and 12, 2021, Oregon Health & Science University together with the International Brain-Barriers Society hosted the 26th Annual Blood-Brain Barrier Consortium Meeting, a virtual gathering with the theme of “Cultivating the Next Generation of Translational Scientists.”
The meeting included presentations on immunotherapy and drug delivery across the blood-brain barrier (BBB) and blood-spinal cord barrier, a poster session, and virtual networking opportunities. Informal discussions covered emerging preclinical research and multicenter clinical research protocols. A funding opportunities roundtable featured representatives from the National Institutes of Health (NIH) and other sources. Young investigators were able to schedule one-on-one mentoring sessions with leading experts in the field.
“Overall, this was an excellent meeting to attend,” said Scott Burks, PhD, Staff Scientist at the NIH Clinical Center. “Attendees include basic biologists, translational researchers, and clinicians, so there was tremendous exposure to all the different facets of BBB biology and pathology and how treatment strategies for CNS diseases are evolving. As a focused ultrasound researcher, it was satisfying to see focused ultrasound garner more attention this year than at previous consortia. In addition to talks and posters about focused ultrasound studies, the technology is certainly gaining attention and earning increasing interest from diverse members of the BBB research community.”
Dr. Burks continued, “Focused ultrasound researchers with interests in BBB disruption also benefit enormously from attending meetings like this. We can easily hyper-focus on disruption strategies that lead to a view of the BBB as a physical impediment to drug delivery, for example, rather than appreciating it as a dynamic physiological system. This consortium delves into BBB biology and medicine where disruption initiates numerous biological processes, many of which remain unknown. This biology will need to be better understood and considered when designing disruption schemes by focused ultrasound or other techniques.”
The Foundation thanks Dr. Burks for providing the following summary of the meeting’s presentations and posters:
Presentations
Immunological Response to Osmotic BBB Disruption
Scott Burks, Bethesda, Maryland
This study evaluated genetic, molecular, and cellular immune responses to BBB disruption by intraarterial hyperosmotic mannitol infusions. Mannitol disruption generates a sterile inflammatory response marked by cytokines, chemokines, and trophic factors as well as inducing reactivity of astrocytes and microglia. In normal brain tissue, this response lasted 48-96 hours. Mannitol generated increased serum levels of cytokines and a delayed inflammatory response in the contralateral brain hemisphere (which was not perfused with mannitol). This is similar to studies that have evaluated neuroinflammation following FUS. Both techniques produce a similar molecular and cellular responses, but those to mannitol were greater in magnitude and longer-lived than those to focused ultrasound. Additionally, effects in the contralateral brain hemisphere (through serum and/or cerebrospinal fluid) were observed with mannitol while focused ultrasound responses appear to remain localized in treated brain volumes. Numerous treatment strategies rely on neuroimmune bioeffects from BBB disruption and while the immunological responses are primarily driven by blood proteins extravasating into the brain (and thus somewhat independent of disruption technique), the location and intensity of responses is dependent on techniques and parameters. Therefore, there might be preferences for various techniques, including focused ultrasound, depending on the degree of immune modulation desired and whether the specific neuropathology is global or focal.
Anticancer Drug Transport at the Blood-Brain Barrier: Impact of the Treatment of Glioblastoma
Julia Schulz, Lexington, Kentucky
This study examined the effects of inhibiting BBB drug transport mechanisms (e.g., p-glycoprotein or multidrug resistance transporters) on the delivery of hydrophobic drugs to the brain. The researchers found that inhibiting these transport mechanisms genetically or pharmacologically, and individually or in combination, resulted in increased brain delivery of numerous different hydrophobic chemotherapies. These results were straight forward, but the study highlights an important point in trans-barrier drug delivery. Many drugs are excluded by the BBB even when it’s open and that delivery can be stymied even with ideal disruption techniques. Situations like these really necessitate strong consideration of BBB physiology and pathology when designing disruption/delivery schemes.
Future of Focused Ultrasound in Brain Tumor Therapy
Joseph Frank, Bethesda, Maryland
This talk was a history and overview of clinical transcranial focused ultrasound techniques and their applications to brain tumor therapy. It covered previous unsuccessful attempts to ablate brain tumors but highlighted more recent investigations examining immunological implications of thermal ablation and the potential to combine ablative focused ultrasound with other immunotherapies. There was substantial focus on BBB and blood-tumor barrier disruption with focused ultrasound and microbubbles. There was a thorough presentation on BBB disruption for chemotherapy delivery using both implantable and noninvasive ultrasound devices. The talk emphasized recent clinical studies that have performed longer-term follow-ups and demonstrated efficacy for ultrasound-based treatment approaches. It concluded by introducing several other applications for which focused ultrasound could assist in brain tumor treatment, such as tumor immune modulation (with either ablation or disruption), additional drug delivery strategies, and noninvasive or “liquid” biopsies.
Posters
13. Morse SV, Chan TG, Long NJ, Choi JJ. Improved Drug Delivery across the BBB with Focused Ultrasound and Microbubble. Imperial College London, London, United Kingdom
This study examined the effects of pulse duration during BBB disruption and drug delivery using focused ultrasound. The authors compared short versus long duration pulses and observed that both protocols permitted similar levels of fluorescent dextran delivery, but that shorter pulses generated more uniform parenchymal distribution, shortened the time that the BBB remained open after sonication, and showed less potential immune activation (less immunoglobulin and albumin within the parenchyma and less dextran uptake by phagocytic brain cells). Altering the number and timing of ultrasound cycles differentially affected the neuro-immunological bioeffects following BBB disruption, thus allowing focused ultrasound protocols to potentially be tailored for different BBB disruption applications.
22. **Straehla JP, Hajal C, Offeddu G, Safford H, Wyckoff J, Kamm RD, Hammond PT. Engineered Nanocarriers to Enhance Drug Delivery across the Blood-Brain Barrier. Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts; Massachusetts Institutes of Technology, Cambridge, Massachusetts
This study outlined the development of an in vitro BBB-glioblastoma platform to evaluate nanoparticle delivery to glioblastomas. The model consisted of glioma spheroids surrounded by endothelial cells, pericytes, and astrocytes. Glioma spheroids were impermeable to nanoparticles, but increased expression of the LDL receptor related protein 1 (LRP1) was found to be highest near the glioma spheroids. Modifying nanoparticle surfaces to target LRP1, increased permeance of nanoparticles into glioma spheroids. This targeting concept was also demonstrated in murine glioma models. This is an encouraging development that in vitro models of BBB with tumors are becoming more sophisticated and useful to evaluate BBB dynamics in ways that will translate in vivo.