Research Spotlight: Exploring Combination Therapy to Improve Outcomes in NF2-Related Schwannomatosis

Lei Xu, MD, PhD, of the Steele Laboratories within the Mass General Brigham Cancer Institute, is the senior author of a paper published in Nature Communications, “NKG2D Upregulation Sensitizes Tumors to Combined Anti-PD1 and Anti-VEGF Therapy and Prevents Hearing Loss.”

Q: What challenges or unmet needs make this study important?

NF2-related schwannomatosis (NF2-SWN) is a rare genetic tumor predisposition syndrome with few treatment options. Patients with this serious condition develop tumors on the nerves responsible for hearing and balance. These tumors typically grow over time and often lead to permanent hearing loss, which profoundly affects communication, independence and quality of life.

Treatment with anti-VEGF antibodies, such as bevacizumab, which block abnormal or harmful blood vessel growth, is associated with tumor shrinkage and hearing improvement in about 30-40% of patients. However, adolescents and young adults are less likely to benefit from this treatment than adults, and most patients ultimately experience tumor growth or hearing loss despite anti-VEGF therapy. For this reason, finding more effective treatments is a major unmet clinical need.

Q: What central question(s) were you investigating?

While immune-based therapies have transformed the treatment of many cancers, their potential has largely been unexplored in non-cancerous tumors, such as the vestibular schwannomas that define NF2-SWN. Our work filled this critical gap by addressing two key questions:

• Does improving blood vessel function in these tumors help immune drugs reach the tumor more effectively and boost their impact?
• And could immune checkpoint therapy offer a new option for patients who do not respond to, or cannot tolerate, the current available therapy, bevacizumab?

Q: What methods did you use and what did you find?

Using mouse models of schwannomas that faithfully reproduce tumor-induced hearing loss, we made several important discoveries. First, we showed for the first time that an immune checkpoint drug, anti-PD-1 antibody, can slow the growth of these non-cancerous tumors and, importantly, help preserve hearing.

Even more striking, combining anti-PD-1 with an anti-VEGF therapy produced far stronger effects than either treatment alone. We found that anti-VEGF therapy normalizes tumor vessel function, allowing immune drugs and immune cells to better access and attack the tumor. This combination approach was also effective against tumors that continued to grow despite anti-VEGF treatment alone, pointing to a powerful new therapeutic strategy.

Q: What are the real-world implications, particularly for patients?

These findings provide a strong foundation for new combination treatment strategies for patients with NF2-SWN. They support pairing immune checkpoint inhibitor therapy with bevacizumab to improve tumor control while protecting hearing.

As additional proof of this combination approach, a recent study from our lab showed that targeted radiation to peripheral nerve tumors can trigger a systemic immune response that works with anti-PD-1 therapy to control tumors in the brain—without directly irradiating the cochlea and risking hearing damage. Taken together, these studies underscore the promise of combination therapies to deliver more effective, hearing-preserving treatment options for patients.

Q: Do you have any follow-up studies planned to validate or build on these findings?

Given the availability of FDA-approved drugs that inhibit PD-1 and VEGF, a clinical trial of this combination is feasible for people with NF2-related schwannomatosis and progressive tumors. In fact, this approach will be tested in a sub‑study of the ongoing Phase II INTUITT‑NF2 trial (NCT04374305) led by Scott Plotkin at Mass General Brigham, using the combination of retifanlimab and bevacizumab.

Authorship: In addition to Xu, Mass General Brigham authors include Simeng Lu, Zhenzhen Yin, Day Caven Blake, Bingyu Xiu, Alona Muzikansky and Scott R. Plotkin. Additional authors include Limeng Wu, Yao Sun, Jie Chen, Lai Man Natalie Wu, Janet L. Oblinger, Lukas D. Landegger, Richard Seist, William Ho, Adam P. Jones, Konstantina M. Stankovic and Long-Sheng Chang.

Paper cited: Lu, S., and Zhen, Y., et al. “NKG2D Upregulation Sensitizes Tumors to Combined Anti-PD1 and Anti-VEGF Therapy and Prevents Hearing Loss.” Nature Communications. DOI: 10.1038/s41467-026-68865-8

Funding: This study was supported by grants from the National Institutes of Health (R01-NS126187, R01-DC020724), the Department of Defense Clinical Trial Award (W81XWH2210439), the Children’s Tumor Foundation Drug Discovery Initiative and Clinical Research Award and the American Cancer Society Mission Boost Award (MBGII-24-1255260-01-MBG to Lei Xu).

Disclosures: None.