Enhanced Tumor Control and Hearing Loss Prevention Achieved with Combined Immune Checkpoint Inhibitor and Anti-VEGF Therapy in Vestibular Schwannoma Model

BackgroundNF2-related schwannomatosis (NF2-SWN) is a debilitating condition that calls for robust treatment options. The defining feature of NF2-SWN is the presence of bilateral vestibular schwannomas (VSs), which grow over time and can result in irreversible sensorineural hearing loss, significantly affecting the quality of life for those affected. At present, there are no FDA-approved medications specifically for treating VS or related hearing loss. VS management involves radiotherapy or surgical resection, while bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (VEGF) may be used off-label in NF2-SWN to shrink the tumor. However, not all patients respond, and the effect is not always durable. There is a critical need for effective medications that can stop the growth of VS and prevent hearing loss associated with these tumors. While immune checkpoint inhibitors have transformed cancer therapy, their potential has not been thoroughly explored in non-malignant tumors such as VS. MethodsWe characterize the effects of anti-PD1 (PD1) treatment on tumor growth and hearing function in two syngeneic, immune-competent VS models. ResultsWe demonstrated that combining VEGF treatment with PD1 significantly enhances the efficacy of each monotherapy. Specifically, i) VEGF enhances PD1 efficacy by normalizing the tumor vasculature to improve drug delivery and immune cell infiltration, and by activating T cell and NK cell anti-tumor cytotoxicity via NKG2D upregulation; and ii) combining PD1 with VEGF treatment effectively controls tumors that progressed despite VEGF treatment. ConclusionThese findings provide a strong foundation for the development of PD1 with VEGF combination therapies for patients with NF2-SWN. Key pointsWe filled a critical gap in NF2 research: 1) we characterized the effects of immunotherapy on tumor growth and hearing function in non-malignant vestibular schwannomas 2) We showed combined anti-VEGF and anti-PD1 enhances the efficacy of each monotherapy Importance of the studyTreatment options for patients with NF2-SWN are limited or are associated with significant co-morbidities. There are no approved medical treatments for NF2-related tumors. While immune checkpoint inhibitors have transformed cancer therapy, their potential has not been thoroughly explored in non-malignant tumors such as VS. Our work filled this critical gap in NF2-SWN research. For the first time, we systemically evaluated ICI efficacy on tumor growth and hearing function in non-malignant schwannomas. Furthermore, we demonstrated that combining VEGF treatment with PD1 significantly enhances the efficacy of each monotherapy. Specifically: i) VEGF enhances PD1 efficacy by normalizing the tumor vasculature to improve drug delivery and immune cell infiltration, and by activating T cell and NK cell anti-tumor cytotoxicity via NKG2D upregulation; and ii) combining PD1 with VEGF treatment effectively controls tumors that progress despite VEGF treatment. Our findings provide a strong foundation for the development of PD1 with VEGF combination therapies for patients with NF2-SWN.