Cerebellopontine Angle (CPA) Model: A Novel Tool for Investigating Immunotherapy in Neurofibromatosis Type 2 Vestibular Schwannomas
Posted May 15, 2019
Lei Xu, M.D., Ph.D., Massachusetts General Hospital
Dr. Lei Xu,
Massachusetts General Hospital
Massachusetts General Hospital
Neurofibromatosis type II (NF2) is a disorder that is typically inherited and characterized by bilateral vestibular schwannomas (VSs), which are benign nervous system tumors composed of neoplastic Schwann cells. VSs cause progressive hearing loss, which often leads to increased social isolation and higher rates of depression, and in some cases, dizziness, facial paralysis, other neuropathies of the cranium, and even mortality. Currently, approved VS and NF2 therapies include surgery and radiation. However, both are accompanied with tremendous risks of worsening existing hearing loss and increasing tumor resistance as a result of further radiation. Bevacizumab has shown promise in VS growth reduction and improved hearing in patients with progressive VSs; however, the hearing improvements are not durable, and issues of tolerability as a result of side effects associated with long-term use remain a challenge. There is an unmet need for NF2 therapies with enhanced efficacy and limited toxicity-associated VS hearing loss. A better understanding of VS progression and hearing loss is essential, but is limited by the lack of animal models for studying the molecular mechanisms and biology of NF2 tumor progression or the manner in which it affects neurological function.
With support from a Fiscal Year 2015 New Investigator Award (NIA) through the Neurofibromatosis Research Program, Dr. Lei Xu and her team are utilizing animal models to evaluate the potential of immunotherapy in controlling tumor progression for enhanced survival. Dr. Xu aims to determine whether the combination of immunotherapy with anti-vascular endothelial growth factor (anti-VEGF) can enhance the delivery of immune checkpoint inhibitors and facilitate activation of immune effector cells for improved treatment efficacy. Preliminary data from Dr. Xu’s group confirms the presence of immune checkpoint molecules in NF2 schwannomas and demonstrates that NF2 patients are in an immune suppressive state. The group has also previously shown that anti-VEGF treatment, via normalizing the abnormal schwannoma vasculature, improves perfusion, reduces tumor hypoxia and significantly enhances radiation efficacy.
Dr. Xu and her team recently published a protocol  on their newly developed cerebellopontine angle (CPA) model for the in vivo study of NF2-related VSs pathophysiology and neurological function. The protocol describes a technique for delivering schwannoma cells into the mouse brain CPA region. This technique opens several avenues for investigating tumor biology, hearing, and neurological function in VSs. The group describes applications of state-of-the-art intravital imaging and hearing assessment techniques for the study of tumor growth and hearing loss. This animal model is a powerful tool in facilitating the study of VS pathobiology through several perspectives, including tumor progression, hearing and neurological function, and facilitates testing the efficacy of novel therapeutics.
Through the NIA, Dr. Xu has developed new techniques, which could be utilized in elucidating the complex biology of NF2 and VS-associated hearing loss. Dr. Xu’s CPA model can also be applied in the study of metastatic lesions, meningiomas, lipomas, and various other CPA disorders. If successful, Dr. Xu’s work will fill the current knowledge gap in the biology of the immune component of VSs, inform on the immune status of NF2 patients, and provide knowledge on the potential efficacy of immunotherapy for NF2-related schwannomas. The findings from this group will also determine the rationale and directly inform the design of future clinical trials for combined immunotherapy with anti-VEGF treatment. This effort has the potential to improve treatment of patients with NF2 VSs through rapid translation to the clinic.
Figure: Establishment of a novel schwannoma cerebellopontine model for evaluation of hearing function in mice. Left: Representative brain MRI and H&E images of the brain of a mouse bearing NF2-/- tumors (white arrow) implanted at the root entry zone of the 8th cranial nerve, located in close proximity to the cochlea (black arrow).
 Chen J, Landegger LD, Sun Y, et al. 2019. A cerebellopontine angle mouse model for the investigation of tumor biology, hearing, and neurological function in NF2-related vestibular schwannoma. Nature Protocols 14(2):541-555.
Last updated Monday, January 3, 2022