A collaborative contingent of researchers from the University of Cincinnati Cancer Center has secured a $40,000 grant from Ride Cincinnati. This funding is designated for an investigation into a slow-release formulation, or wafer, of an immune-stimulating agent. The objective is to invigorate the central nervous system’s (CNS) immune defenses following surgical intervention to excise glioblastoma, a particularly aggressive form of primary brain cancer.
Dr. Jonathan Forbes, the principal investigator steering this initiative, elucidated that glioblastomas represent the most prevalent category of primary brain neoplasms. The five-year survival rate for patients diagnosed with glioblastoma hovers between a stark 5% and 7%.
For numerous decades, the identification of effective therapeutic strategies for these formidable tumors has been a significant challenge, primarily due to two principal obstacles:
– The protective blood-brain barrier, which typically shields the brain from pathogenic microorganisms, simultaneously impedes the passage of high-molecular-weight therapeutic agents into proximity with tumor cells.
– The CNS is characterized by an immunologically quiescent microenvironment, rendering it more difficult to elicit a robust immune response capable of eradicating cancerous cells that have infiltrated healthy brain tissue and cannot be entirely removed via surgery.
Currently, neurosurgical procedures may involve the placement of wafers that deliver either cytotoxic radiation or broad-spectrum chemotherapeutic agents. However, Dr. Forbes noted that these interventions lack specificity, are associated with substantial costs, and have not demonstrably yielded significant improvements in patient prognoses.
“Upon the surgical excision of the tumor, we gain unobstructed access to the resection cavity, which we recognize is microscopically permeated by neoplastic cells,” stated Dr. Forbes, who holds the positions of associate professor and residency program director within the Department of Neurosurgery at UC’s College of Medicine and practices as a neurosurgeon at the UC Gardner Neuroscience Institute. “It stands to reason that we should leverage this access to bolster the central nervous system‘s capacity to eliminate any remaining malignant cells.”
Medical student Beatrice Zucca elaborated that the initial phase of the project involved identifying an immune-stimulating molecule possessing the requisite safety profile and potency to activate the brain’s endogenous immune system. The team ultimately selected a protein known as Interleukin-15 (IL-15).
“IL-15 exhibits exceptional efficacy in activating immune cell populations that are indispensable for identifying and eliminating neoplastic cells,” commented Ms. Zucca, who served as a neurooncology research fellow under Dr. Forbes’s guidance during the preceding autumn. “It enhances their viability, augments their proliferation, and amplifies their cytotoxic capabilities, thereby positioning it as an optimal candidate for orchestrating a concerted immunological assault against a highly recalcitrant malignancy like glioblastoma.”
The grant funding will facilitate the team’s endeavor to assess the actual immune-stimulating efficacy of the preparation through the utilization of glioblastoma-on-a-chip technology, developed in collaboration with Dr. Ricardo Barrile.
“An organ-on-a-chip represents a miniaturized facsimile of a living organ, engineered to encompass the minimal biological components necessary to recapitulate specific pathological conditions,” explained Dr. Barrile, an assistant professor of biomedical engineering in UC’s College of Engineering and Applied Science. “Rather than evaluating therapeutic agents in conventional flat plastic culture dishes or relying exclusively on animal models—which frequently fall short in predicting human responses owing to genetic dissimilarities—we employ three-dimensional bioprinting and microfluidics to construct a living model of a human organ.”
Dr. Barrile’s laboratory achieved the distinction of being the first to construct a model that seamlessly integrates human neural cells with glioblastoma cells, utilizing a fusion of conventional 3D printing and bioprinting techniques. The glioblastoma-on-a-chip model further incorporates a bioprinted vascular channel designed to simulate the pharmacokinetics of drug transport from the circulatory system to the brain, alongside a separate channel engineered to replicate the immune system’s functions.
“This affords us a ‘human-relevant’ platform for the safe and precise evaluation of novel therapeutics prior to their administration to patients,” Dr. Barrile affirmed. “The integration of the immune system was the crucial missing element and is paramount for accurately reflecting the inherent composition of glioblastoma, which typically comprises up to 30% immune cells within a patient. These vital cellular components are frequently lost during standard in vitro cell culturing.”
While the current phase of this research is primarily focused on elucidating the wafer’s impact on the immune response directed at glioblastoma cells, it also holds the potential to advance the validation of Dr. Barrile’s glioblastoma-on-a-chip model as a sophisticated tool for personalized medicine.
“We are in the process of developing a platform that could ultimately predict an individual patient’s specific response to immunotherapy. By utilizing a patient’s own cellular material within our chip construct, we can identify the most efficacious therapeutic strategy for that particular individual preceding the commencement of treatment,” Dr. Barrile stated. “Essentially, we are transitioning from a generalized, one-size-fits-all approach to a highly individualized, bespoke strategy.”
Dr. Forbes also highlighted that, in parallel with this research, the UC Brain Tumor Center is concurrently investigating an alternative strategy to surmount the impediments posed by the blood-brain barrier. This involves navigated focused ultrasound technology, capable of temporarily permeabilizing this protective interface.
“It is remarkably encouraging that we are pursuing advancements on both these fronts at the University of Cincinnati, with the shared aim of discovering superior therapeutic interventions for glioblastoma,” Dr. Forbes expressed.
Ms. Zucca conveyed that the multidisciplinary nature of this research has been profoundly significant, both from a scientific and a personal perspective.
“The convergence of molecular immunology, biomedical engineering, and clinical neurooncology has had a transformative effect on my development as a scientific investigator,” Ms. Zucca remarked. “Most importantly, it represents a tangible stride towards therapeutic modalities that harness the patient’s own immune system to confront one of the most aggressively challenging cancers known to medicine.”
Additional contributors to this project include Kevin Haworth and David Plas.
