NKG2D Upregulation Enhances T and NK Cell Cytotoxicity, Sensitizes Tumors to Combined αPD1 and αVEGF Therapy, and Contributes to Hearing Loss Prevention in Vestibular Schwannoma Model

Background: NF2-related schwannomatosis (NF2-SWN) is a debilitating condition that calls for robust treatment options. NF2-SWN is characterized by 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 monoclonal antibody (αVEGF), has been 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 VS growth and associated hearing loss. While immune checkpoint inhibitors have transformed cancer therapy, their potential has not been thoroughly explored in non-malignant tumors such as VS. Methods: We characterize the effects of combined anti-programmed cell death protein-1 (αPD1) and αVEGF treatment on tumor growth and hearing function in two syngeneic, immune-competent VS models. Results: Combining αVEGF with αPD1 treatment significantly enhances the antitumor efficacy of each monotherapy. Specifically, i) αVEGF augments αPD1 efficacy by normalizing tumor vasculature to improve drug delivery and immune cell infiltration, and by activating the antitumor cytotoxicity of T and NK cells via NKG2D upregulation; and ii) combined αPD1 with αVEGF treatment effectively controls the growth of tumors that progressed despite αVEGF treatment. Conclusion: These findings provide a strong foundation for the αPD1 with αVEGF combination therapies to treat patients with NF2-SWN.