Intranasal Delivery of Oncolytic HSV in Pediatric Glioma
High-grade gliomas (HGGs) are the most common cause of cancer-related death in children and diffuse midline gliomas (DMGs) are the most rapidly fatal HGGs with a median survival of less than 12 months. Despite numerous clinical trials involving aggressive therapies, there has been no meaningful improvement in patient survival in over two decades. Factors that contribute to the dismal prognosis of DMG include their invasive nature and anatomic location in an important area of the brain preclude surgical resection, and inability to deliver medications across the blood-brain barrier (BBB) that limits of the distribution of drugs given orally or through the blood vessel to reach the tumor. Therapeutic delivery by direct injection into a tumor is invasive, expensive, and has substantial surgical risks. We propose to develop and evaluate intranasal delivery as innovative drug delivery strategy capable of bypassing the BBB and enhancing the therapeutic delivery to the brain tumors. Immunotherapy has been effective for a variety of solid tumors, and studies suggest that immunotherapy can be effective for pediatric glioma through recruitment and activation of immune cells that stimulate an anti-tumor immune response. We propose to integrate an effective and noninvasive delivery system, intranasal delivery, with an altered cold-sore virus, an immunotherapy that has shown great promise in early phase clinical trials but is currently limited by the requirement for intratumoral delivery.
Project Goals
The primary goal of this project is to integrate an effective and noninvasive delivery system, intranasal delivery (IND) with oncolytic herpes simplex virus (oHSV), which has shown great promise in early phase clinical trials but is currently limited by the requirement for intratumoral delivery. IND approach will facilitate the ability to give repeated, maximum doses of oHSV that can target DMG cells obviating the need for repeated surgical procedures and without damaging healthy tissues. We hypothesize that IND oHSV will safely deliver cold-sore virus to brain tumors and achieve greater tumor cell killing through repeated treatments without damaging healthy brain and removing the need for intratumoral delivery. This new therapeutic approach would improve not only the therapeutic benefit, but also perhaps the quality of life of children that are afflicted with this highly morbid brain cancer. The successful completion of this high-risk, high-reward proposal will lay the foundation for clinical trials of this approach with the ultimate goal of changing how we treat DMG away from toxic, marginally effective therapies to a less-toxic, noninvasive, more effective targeted immunotherapy, which will significantly improve quality of life and outcomes of patients with DMG. Such a clinical trial can be implemented quickly (within 2-3 years following completion of this proposal study).
