VEGF Receptors Peptide Vaccine in Neurofibromatosis Type 2: A Single-Arm, Open-Label, Phase 1/2 Trial
72 Pages Posted: 2 Mar 2019More...
Background: There is no established therapy for neurofibromatosis type 2 (NF2). Bevacizumab has recently proved efficacious for the treatment of NF2, presumably because vascular endothelial growth factor (VEGF) is essential for NF2 tumor growth. Theoretically, VEGF receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. The aim of the current study was to evaluate the safety and efficacy of a VEGFRs peptide vaccine in NF2 patients.
Methods: An exploratory clinical study of VEGFRs peptide vaccine was conducted in 7 patients with progressive NF2-derived schwannomas. Tumor volume and blood flow were analyzed via magnetic resonance imaging and computed tomography perfusion, and hearing was evaluated via word recognition scores (WRSs) and pure-tone audiograms. To investigate the therapeutic mechanisms involved in this novel therapy, CTL responses and VEGFRs expression in schwannomas were analyzed.
Findings: Hearing improved in 3 of the 6 assessable patients (50%), with WRS increases of more than 10%. Reductions of > 20% in more than one tumor were observed in 2 patients, including a case in which bevacizumab had not been effective (case 6). There were no severe adverse events related to the vaccine. Both VEGFR1 specific and VEGFR2-specific CTLs were induced in 6 patients, and in the remaining patient VEGFR1-specific CTLs were induced. Histological analysis of schwannomas revealed high VEGFRs expression both in tumor vessels and in tumor cells. Surgery was performed after vaccination in two patients, and significant reductions in VEGFRs expression in schwannomas were observed.
Interpretation: This is the first clinical immunotherapy study demonstrating the safety and efficacy of VEGFRs peptide vaccination in patients with NF2.
Trial Registration Number: The trial was registered at UMIN (UMIN000023565).
Funding Statement: The authors state: "None."
Declaration of Interests: The authors have no personal financial or institutional interests in any of the drugs, materials, or devices mentioned in this article.
Ethics Approval Statement: All protocols were approved by the Keio University Ethics Committee, and conducted in accordance with the Helsinki declaration on experimentation on human subjects.
Keywords: VEGF receptor; peptide vaccine; NF2; schwannoma: meningioma
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