Noninvasive Double Microbubble Delivery Approach Marks Breakthrough in Brain Cancer Treatment

Glioblastoma (GBM) is an extremely aggressive and invasive form of primary brain cancer, widely regarded as incurable. As a “cold tumor,” GBM possesses a tumor microenvironment that hinders immune activity and reduces responsiveness to treatment. While some therapies can slow down tumor growth and relieve symptoms, they fail to stop the disease’s inevitable advancement. GBM has a recurrence rate exceeding 90% within six to nine months following initial treatment. When the tumor returns, it is typically more resistant to interventions such as chemotherapy and radiation, ultimately leading to patient death. Now, researchers have uncovered a potentially groundbreaking method to address GBM, the deadliest brain cancer type for which no curative therapies currently exist.

Researchers at VCU Massey Comprehensive Cancer Center (Richmond, VA, USA) have developed a novel molecule capable of delivering a dual treatment effect—cytotoxicity and immunotoxicity—to eliminate tumors while activating the immune system to help prevent GBM recurrence. This approach involves a “Fusion Superkine” (FSK), a molecule combining two therapeutic cytokines in one construct. The researchers implemented a dual-targeting treatment strategy by designing the FSK using two distinct components: a cytotoxic element and an immune-regulating molecule. Administered intravenously, the FSK selectively delivers two immune-stimulating cytokines—secreted proteins that regulate the activity and development of numerous cell types, including immune cells. One cytokine initiates targeted tumor cell destruction, while the other modulates the immune response, collectively attacking the traits that make GBM particularly difficult to manage.

To achieve this, the researchers engineered a unique FSK by merging the tumor-killing properties of a next-generation version of melanoma differentiation associated gene-7/Interleukin-24, known as IL-24S (Superkine), with improved stability, secretion, and biological activity, and the immune-stimulating function of IL-15, to optimize the therapeutic effect. In a mouse model of GBM with a functioning immune system, the FSK led to significantly greater tumor shrinkage and increased survival compared to treatment with IL-24S or IL-15 alone. The treatment not only destroyed GBM cells but also promoted the infiltration of T cells, dendritic cells (DCs), macrophages, and NK cells into the tumor, key immune cells that collectively work to destroy cancerous tissue. To deliver the FSK effectively, researchers used a type 5 adenovirus (Ad.5) engineered to express the fusion protein and then created a new delivery technique combining focused ultrasound (FUS) and microbubbles (MBs), known as the FUS-DMB strategy, to bypass the blood-brain barrier (BBB) and improve the precision of systemic viral delivery.

The BBB, composed of tight junctions in endothelial cells, prevents most substances from entering the brain, limiting the effectiveness of conventional chemotherapy and cancer treatments. However, the FUS-DMB method allows the stealthy delivery of the Ad.5-FSK through the bloodstream while temporarily and safely opening the BBB, enabling the FSK to reach the tumor and exert its therapeutic effects. This dual microbubble-based strategy also holds promise for delivering viruses and genetic treatments to other types of tumors. The FUS-DMB platform enhances the penetration of therapeutic molecules into designated tissues beyond the brain, resulting in improved molecular drug delivery and superior treatment outcomes. Further studies are planned to evaluate the application of FSK in clinical tumor samples and eventually in human patients.

“Our novel systemic therapy for brain cancer incorporates a unique immune-therapeutic agent, a ‘Fusion Superkine’ (FSK), and an innovative viral systemic delivery approach, focused ultrasound double microbubble (FUS-DMB), which permits safe and effective targeted delivery through the blood-brain barrier (BBB) into the brain,” said one of the study’s senior authors, Paul B. Fisher, MPh, Ph.D., FNAI. “The bottom line is that in the future we may be able to treat both primary brain tumors (glioblastoma) and secondary brain tumors (arising from metastases outside of the brain) non-invasively without surgery.”

Related Links:
VCU Massey Comprehensive Cancer Center