Angiogenesis as a target of treatment
As discussed in NF2 gene function, merlin affects multiple pathways involved in cell growth, which can help to identify different therapeutic targets. Although VS is a benign tumor and grows relatively slowly, angiogenesis is required for the tumor to expand beyond a specific size37,38). Some angiogenesis-stimulating factors were identified, and among the most well-known is vascular endothelial growth factor (VEGF). A correlation has been found between the degree of VEGF expression and clinical parameters such as tumor growth, tumor volume, and microvessel density38,39). Currently, a number of translational research efforts for therapeutic targeting of VEGF or VEGF receptors have been conducted; the main ones are discussed below. Table 2 summarizes reports regarding other molecular-targeted therapies.
Table 2. Recent clinical trials for NF2-related VS
Bevacizumab, an anti-VEGF monoclonal antibody, is already approved for clinical use, including in Japan, for treating malignant gliomas and other carcinomas. Plotkin et al. investigated the effect of bevacizumab in NF2-related VS for the first time, showing a reduction in tumor volume in 9 of 10 patients and improved hearing in some cases40). Other reports showed the efficacy of bevacizumab in NF2-related VS41-43). Goutagny et al. reviewed the literature and reported that bevacizumab improved hearing and tumor shrinkage in more than 50% of progressive VS44). A study of bevacizumab administration in NF2-related VS in Japanese patients showed a maximum decrease in tumor volume to baseline occurring three months after receiving four doses of bevacizumab (5 mg/kg in two-week intervals)45). However, increasing the bevacizumab dose from 5 mg/kg every two weeks to 10 mg/kg was found to be ineffective46). The problem with bevacizumab therapy is the need for long-term administration for tumor control, which can result in side effects, including hypertension, proteinuria, and delayed wound healing.
Currently, a randomized, double-masked, placebo-controlled, multicenter trial to assess bevacizumab's efficacy and safety in NF2 patients is ongoing in Japan, with sixty patients already included with the evaluation of hearing improvement in the affected ear as the primary objective47). This study is the first of its kind regarding the administration of bevacizumab in NF2 in a randomized controlled trial. It is also the most extensive prospective study of this rare and intractable disease, and the results are eagerly awaited. For this randomized control trial, 12 other Japanese institutions have joined the principal investigators at Fukushima Medical University.
Peptide vaccine therapy for VEGF receptor
Another study investigating the development of peptide vaccines targeting the VEGF receptor (VEGFR) as a novel therapy is also underway in Japan. High VEGFR (VEGFR1 and VEGFR2) expression was detected on endothelial cells and tumor cells in NF2 schwannomas48). Thus, a subcutaneous injection of VEGFRs combined with a human leukocyte antigen (HLA) peptide vaccine could activate cytotoxic T lymphocytes (CTLs) specific for these and exert an antitumor effect. The CTLs attack tumor cells and blood vessels directly and are maintained as acquired immunity, expected to be a long-term effect. A Japanese clinical study showed that CTLs against both VEGFRs were induced in 6 out of 7 patients with eight doses of the peptide vaccine. Hearing improved in 40% of patients. Twenty-two out of 23 schwannoma lesions were reduced or had no change, but only one cystic schwannoma became enlarged. Furthermore, tumor specimens obtained from pre- and post-vaccination showed that the vaccination caused both loss of VEGFR expression and reduction of VEGF-A expression49).
Since this vaccine consists of HLA-A-binding peptides, some patients with different HLA-A types cannot induce an immune response to VEGFR. It is expected that the number of patients eligible for this kind of therapy could increase with the development of peptide vaccines mixed with certain common HLA types to compensate for the variations available in the population.