Adding Immunotherapy to Neurofibromatosis Treatment May Mitigate Hearing Loss

The addition of an immunotherapy may prevent serious hearing damage related to radiotherapy that treats tumors associated with neurofibromatosis 2 (NF2), according to a study published by PNAS Plus.

The researchers found that crizotinib inhibited a molecular pathway that improved the radiosensitivity of tumors in mice models of the genetic disease, which lead to a reduced dose. The treatment also was observed to stop the growth of cultured cancer cells from patients with NF2.

Additionally, the authors developed a new mouse model that better mimics NF2 hearing loss and a system for culturing NF2 tumor cells.

“The hallmark of NF2 are intracranial tumors called vestibular schwannomas, which typically lead to profound hearing loss,” said co-corresponding author Lei Xu, MD, PhD. “For most patients, hearing loss is the most disabling symptom of these tumors, and the primary treatments for growing tumors—surgery and radiation therapy—can further damage hearing. The development of a novel therapeutic strategy with enhanced efficacy and minimal treatment-related hearing loss is urgently needed.”

Patients with NF2 develop benign tumors throughout the nervous system and the condition most commonly affects the eighth cranial nerve, according to the authors. Since this nerve affects hearing, the vestibular schwannomas can lead to total hearing loss.

In prior studies, the team of researchers found that treatment with bevacizumab immunotherapy improved hearing among patients with NF2; however, improvements were not long-lasting and not all patients experienced gains in hearing.

Another study showed that bevacizumab improved hearing among patients with NF2 who had low levels of hepatocyte growth factor (HGF), which has been found to be involved with the oncogene, cMET.

In the current study, the authors first confirmed in mice that radiation therapy activates cMET and leads to drug resistance. Then, they used crizotinib to block cMET signaling in 2 different mice models of NF2: the standard model in which NF2 cells are injected into the eighth cranial nerve and a new model in which schwannoma cells are implanted into the nerve.

The authors noted that the new model resulted in the hearing loss experienced by humans with NF2.

In both types of mice, the addition of crizotinib blocked the HGC-cMET pathway and improved treatment response. The treatment achieved this by boosting radiation-related DNA damage, reduced tumor growth, and increased survival, according to the study.

The researchers found that knocking out cMET resulted in similar findings.

Through the new mouse model, the study also revealed that inhibiting cMET did not have ill effects on the hearing of mice, according to the author.

Further, the authors developed an optimal system for culturing schwannoma cells from human patients with NF2. This approach maintained the cells for up to 3 weeks.

With the new model, the researchers found that HGF expression and cMET activation was linked to tumor growth and that blocking the pathway inhibited cancer growth.

“With this new culture model, we can screen libraries of drugs for anti-tumor activity,” said co-corresponding author Rakesh Jain, PhD. “These methods and tools will address a major bottleneck in the NF2 field by providing robust, expandable and biologically diverse cellular models that recapitulate the defining features of this and other human diseases.”

Since crizotinib is approved to treat lung cancer, these findings may be able to be used in clinical practice, according to the authors.

“NF2 is a disease that need new solutions, and our findings provide compelling rationale that paves the road for clinical testing of this combined therapy to treat vestibular schwannomas in human patients,” Dr Xu said.