Characterizing the effects of anti-PD1 immunotherapy on ataxia in a vestibular schwannoma mouse model.

PURPOSE: Vestibular schwannoma (VS) is a non-malignant tumor arising from Schwann cells of the vestibulocochlear nerve. While not malignant, VS can significantly impact patients’ quality of life by causing hearing loss, facial paralysis, vestibular dysfunction, and impaired mobility. The resulting ataxia is particularly debilitating, often resulting in significant gait disturbances and an increased risk of falls. Current treatment options, including surgery and radiotherapy, carry risks of further damaging the surrounding cranial nerves, underscoring the need for more effective and less invasive therapeutic strategies. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their potential in non-malignant tumors like VS remains unexplored. Immune-related adverse events, particularly neurological complications such as neuroinflammation and brain edema, pose challenges for their application in VS. In this study, we aimed to evaluate the effects of anti-PD1 (αPD1) treatment on neurological symptoms.

METHODS

In the cerebellopontine angle model of VS that reproduces schwannoma-induced ataxia, we used a panel of tests to evaluate the efficacy of αPD1 monotherapy and combination therapy with anti-VEGF (αVEGF) on alleviating ataxia.

RESULTS

Our results demonstrated that αPD1 treatment alleviated ataxia in mice but also triggered a systemic immune response, leading to brain edema and inflammation. To mitigate these adverse effects and optimize αPD1 therapy, we investigated combination strategies. αVEGF treatment, known for its ability to normalize tumor vasculature, can reduce vasogenic edema of the brain and peripheral nerve and improve neurological function in VS models. Here, we demonstrated that combined αPD1 and αVEGF therapy significantly improved ataxia and inhibited the activation of the inflammatory AKT and JAK2/STAT3 signaling pathways (n=18 mice/arm in animal studies).

CONCLUSION

These findings suggest that a combinatorial approach using αVEGF and αPD1 may reduce immunotherapy-induced neuroinflammation and neurotoxicity, offering a promising therapeutic strategy for VS management.