A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2

Tamura, Ryota; Fujioka, Masato; Morimoto, Yukina; Ohara, Kentaro; Kosugi, Kenzo; Oishi, Yumiko; Sato, Mizuto; Ueda, Ryo; Fujiwara, Hirokazu; Hikichi, Tetsuro; Noji, Shinobu; Oishi, Naoki; Ogawa, Kaoru; Kawakami, Yutaka; Ohira, Takayuki; Yoshida, Kazunari; Toda, Masahiro

doi:10.1038/s41467-019-13640-1

Cited by 35 publications

(45 citation statements)

References 49 publications

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“…We have previously conducted exploratory clinical studies investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens in patients with recurrent high-grade gliomas [16,17]. Recently, VEGFRs peptide vaccine was used in patients with progressive neurofibromatosis type 2 (NF2) [18]. In the study, the number of Foxp3-positive regulatory T cells (Tregs) decreased after the vaccination, suggesting that the CTLs induced by the vaccination can directly kill a wide variety of cells associated with tumor growth, including tumor vessels, tumor cells, and Tregs expressing VEGFR1 and/or VEGFR2.…”

Section: Introductionmentioning

confidence: 99%

Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - a case series

et al. 2020

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Background: The expression of vascular endothelial growth factor (VEGF)-A/ VAGF receptors (VEGFRs) signaling plays a pivotal role in the tumor angiogenesis and the development of the immunosuppressive tumor microenvironment in glioblastomas. We have previously conducted exploratory clinical studies investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens in patients with recurrent high-grade gliomas. Recently, an exploratory clinical investigation of VEGFRs peptide vaccination was conducted in patients with progressive neurofibromatosis type 2. Those studies suggested that cytotoxic T lymphocytes (CTLs) induced by the vaccination can directly kill a wide variety of cells associated with tumor growth, including tumor vessels, tumor cells, and immunosuppressive cells expressing VEGFR1 and/or 2. In the present study, synergistic activity of the combination of VEGFRs peptide vaccination with chemotherapy was evaluated. Methods: We performed the first clinical trial to assess VEGFR1 and 2 vaccination along with temozolomide (TMZ)-based chemoradiotherapy for the patients with primary glioblastomas. Furthermore, histopathological changes after the vaccination were evaluated using paired pre-and post-vaccination specimens. Results: The disappearance of radiographically enhanced lesion was observed in 2 patients after the vaccination, including one in which the methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was not observed. The histopathological findings of pre-and post-vaccination specimens demonstrated that tumor vessels showed negative or slight VEGFRs expressions after the vaccination and most endothelial cells were covered with PDGFR-β-positive pericytes. Notably, CTLs induced by VEGFRs peptide vaccination attacked not only tumor vessels but also tumor cells and regulatory T cells expressing VEGFRs even in recurrent tumors. Conclusions: VEGFR1 and 2 vaccination may have a preliminary synergistic effect when administered with TMZ. The limitation of the present study was the paucity of the number of the samples. Further studies involving more patients are warranted to confirm the findings of this study. Trial registration: This study was registered as UMIN000013381 (University Hospital Medical Information Network-Clinical Trial Registry: UMIN-CTR) on 5 March, 2014 and with the Japan Registry of Clinical Trials (jRCT) as jRCTs0311 80170 on 1 March, 2019.

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Section: Introductionmentioning

confidence: 99%

Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - a case series

et al. 2020

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“…Our exploratory clinical trial also demonstrated that VEGFRs peptide vaccination showed hearing improvement and tumor volume reduction in NF2 patients. There were no severe adverse events related to the vaccine [ 15 ]. Recently, we initiated another clinical trial using a VEGFRs peptide vaccine for recurrent, progressive, and refractory benign brain tumors (hemangiopericytoma, hemangioblastoma, meningioma, chordoma, and ependymoma).…”

Section: Discussionmentioning

confidence: 99%

“…None of the patients had a potentially relevant past medical history, such as vasculopathy, in the Vac and Vac + Bev groups. Data from CTL induction were also collected, which were evaluated by the contract research organizations “OncoTherapy Science, Inc. (Kanagawa, Japan) and “Cancer Precision Medicine, Inc. (Kanagawa, Japan)””, as previously described [ 15 , 32 ]. To assess the relationship between the clinical information and the adverse events in the Vac + Bev group, and to evaluate the adverse event rate among these groups, the chi-squared test was used.…”

Section: Methodsmentioning

confidence: 99%

“…They were associated with favorable event-free survival and improvement of peritumoral edema, leading to a better patient performance status [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Bev is currently used most frequently in the management of glioblastomas [ 14 , 15 ]. However, clinical trials using these anti-angiogenic agents have suggested that the favorable clinical effects on patients’ performance status do not translate into an overall survival benefit.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously conducted exploratory clinical trials investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens, such as lymphocyte antigen 6 family member K (LY6K), DEP domain containing 1 (DEPDC1), kinesin family member 20A (KIF20A), and forkhead box M1 (FOXM1), in patients with primary and recurrent malignant gliomas, wherein treatment exhibited safety and yielded therapeutic effects in some patients [ 14 , 22 , 23 ]. Recently, in our hospital, a clinical trial using a VEGFRs peptide vaccine was also conducted in patients with progressive neurofibromatosis type 2 (NF2)-derived schwannomas, showing hearing improvement and tumor volume reduction [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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A Pilot Study of the Adverse Events Caused by the Combined Use of Bevacizumab and Vascular Endothelial Growth Factor Receptor-Targeted Vaccination for Patients with a Malignant Glioma

et al. 2020

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Anti-angiogenic therapy, targeting vascular endothelial growth factor (VEGF)-A/VEGF receptors (VEGFRs), is beneficial for tumor growth prevention in a malignant glioma. A simultaneous blockade using both bevacizumab (Bev), which targets circulating VEGF-A, and a multi-kinase inhibitor on VEGFRs was more effective for advanced solid cancers, including melanoma and renal cell carcinoma. However, previous clinical trials demonstrated a high adverse event rate. Additionally, no studies previously assessed treatment efficacy and safety using both VEGF-A and VEGFR-targeted agents for malignant gliomas. We had conducted clinical trials investigating VEGFRs peptide vaccination in patients with malignant gliomas, in which the treatment exhibited safety and yielded therapeutic effects in some patients. The combined use of Bev and VEGFRs vaccination may enhance the anti-tumor effect in malignant gliomas. In this pilot study, the adverse event profile in patients treated with Bev after the vaccination was investigated to establish this treatment strategy, in comparison to those treated with Bev collected from the published data or treated with the vaccination alone. In our previous clinical studies on patients with malignant gliomas, Bev was administered to 13 patients after VEGFRs vaccinations. One patient had a Grade 4 pulmonary embolism. Two patients had Grade 2 cerebral infarctions. There were no significant differences in the adverse event rates among patients treated with Bev, with the vaccination, or with Bev after the vaccination. Although careful observation is imperative for patients after this combination treatment strategy, VEGFRs-targeted vaccination may coexist with Bev for malignant gliomas.

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Management of Painful Conditions Associated with Nerve Tumors

Filley

Winfree

2021

Diagnostic Assessment and Treatment of Peripheral Nerve Tumors

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A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2

Cited by 35 publications

References 49 publications

Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - a case series

Clinical and histopathological analyses of VEGF receptors peptide vaccine in patients with primary glioblastoma - a case series

A Pilot Study of the Adverse Events Caused by the Combined Use of Bevacizumab and Vascular Endothelial Growth Factor Receptor-Targeted Vaccination for Patients with a Malignant Glioma

Management of Painful Conditions Associated with Nerve Tumors

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