DDEL-14. Optimizing dose interval and formulation of neural stem cell-delivered Oncolytic adenovirus therapy for high-grade glioma

Abstract High-grade gliomas are the most common and lethal brain tumors, with a median survival of only 14 months despite aggressive standard of care treatment – surgical resection, radiation, and chemotherapy. Recurrent gliomas fare worse, with average survival under 8 months. The five-year survival rate is a dismal 6.9%. Innovative approaches are urgently needed. Human neural stem cells (NSCs) home to glioma sites, enabling targeted delivery of therapeutic agents. One such agent, CRAd-S-pk7, is a conditionally replicating oncolytic adenovirus driven by the survivin promoter, which selectively lyses glioma cells while sparing normal tissue. Tumor cell lysis leads to viral amplification and stimulates anti-tumor immunity. However, delivery of the free virus is limited by neutralizing antibodies and complement-mediated inactivation. To overcome these limitations, we use an allogeneic, tumor-tropic NSC line (HB1.F3.CD21) as a delivery vehicle. This approach protects the virus, enhances tumor-specific amplification, and improves distribution and therapeutic efficacy. A first-in-human trial combining single-dose NSC.CRAd-S-pk7 with standard chemoradiation for newly diagnosed glioma patients at Northwestern University and City of Hope showed safety and potential efficacy (2021 Lancet Oncology), prompting an ongoing phase lb multi-dose study. A City of Hope led dose escalation, multi-dose, multi-site phase I NSC.CRAd-S-pk7 recurrent glioma study is ongoing. Here, we present preclinical results comparing two NSC.CRAd-S-pk7 dose formulations administered at varying dose intervals. Our aim is to identify a regimen that maximizes therapeutic efficacy by balancing viral-induced immune activation while avoiding T-cell exhaustion. These studies inform next-phase clinical trial design and represent a key step toward optimizing this promising therapeutic platform.