Next generation intraventricular immunovirotherapy for the treatment of leptomeningeal disease

• Applicant: Dr. Lennard Spanehl
• Subject Area: Pharmacology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534053725

Malignant brain tumors/metastases are associated with extreme morbidity/mortality and therefore require more effective therapies to improve clinical outcomes. Oncolytic herpes simplex virus (oHSV) therapy has shown promising results in clinical trials. oHSVs have been successfully engineered to introduce mutations that prevent a productive infection in normal brain cells while maintaining the virus’ oncolytic activity against cancer cells. The oncolytic effect of the virus and the anti-tumor immune response that the virus stimulates provide dual mechanisms of attacking cancer cells. This approach has already shown great promise in multiple phase I trials of first-generation oHSVs in adults with high-grade gliomas and in a recently completed phase I trial of oHSV G207 for pediatric brain tumors (NCT02457845). Direct intratumoral inoculation delivers concentrated virus directly to tumor cells but requires an invasive neurosurgical procedure that limits repeat injections efficiently and precludes direct targeting of metastatic and leptomeningeal disease (LMD). Intraventricular delivery of oHSV would overcome these limitations but has been avoided due to toxicity concerns. Herein, we will seek to determine if toxicity from intraventricular oHSV rQNestin can be mitigated with protective preconditioning approaches that enable effective treatment of disseminated breast cancer. This proposal seeks to examine the ability of a next generation oHSV (rQNestin) to target LMD caused by metastatic disease (breast cancer). In so doing, we will seek to understand the ability of rQNestin to be safely delivered to the cerebrospinal fluid spaces and therapeutically engage models of LMD. Our approach may ultimately yield a novel/clinically relevant approach capable of treating LMD and/or disseminated disease throughout the central nervous system. If successful, such preclinical safety/efficacy data would be highly translatable and support future clinical trials centered on this approach. In addition, this proposal seeks to develop next generation smart materials/devices capable of facilitating repeat dosing of oHSVs within the central nervous system whilst minimizing the number of invasive surgical procedures. Specifically, we will seek to understand the stability of clinically relevant oHSVs and their capacity for extended delivery/release; screen and develop ideal hydrogel(s) capable of carrying/releasing oHSVs within tumor beds/resection cavities; design, develop and test a microdevice capable delivering oHSVs within the ventricles (i.e., to the CSF) and tumor resection cavities. Our approach will ultimately generate next generation materials and devices capable of delivering multiple doses of oHSVs within the brain and spinal cord. This work also has the potential to serve as a platform technology for the delivery of a litany of additional approved and experimental therapeutics within the central nervous system.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Hosts: Dr. Joshua D. Bernstock, Ph.D.; Professor Dr. E. Antonio Chiocca