A pilot study of peptide vaccines for VEGF receptor 1 and 2 in patients with recurrent/progressive high grade glioma

Shibao, Shunsuke; Ueda, Ryo; Saito, Kei; Kikuchi, Ryogo; Nagashima, Hideaki; Kojima, Atsuhiro; Kono, Hiroshi; Pareira, Eriel Sandika; Sasaki, Hidenao; Noji, Shinobu; Kawakami, Yutaka; Yoshida, Kazunari; Toda, Masahiro

doi:10.18632/oncotarget.25131

Cited by 24 publications

(20 citation statements)

References 54 publications

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“…TGF-β inhibits the immune system so as to protect tumor cells from being killed by immune cells [ 34 ]. The increase of VEGF levels in tumors reduces the immune function and promotes the formation of tumor interstitial blood vessels, allowing the tumors to grow rapidly [ 35 , 36 ]. IL-6 stimulates the proliferation, differentiation, and function of cells involved in the immune response [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

MiR-218 produces anti-tumor effects on cervical cancer cells in vitro

Zhu¹,

Tu²,

Liang³

et al. 2018

World J Surg Onc

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BackgroundAs indoleamine-2,3-dioxygenase 1 (IDO1) is critical in tumor immune escape, we determined to study the regulatory mechanism of miR-218 on IDO1 in cervical cancer.MethodsReal-time PCR (RT-qPCR) was carried out to measure the expression of miR-218. RT-qPCR and Western blot were performed to detect the expression of IDO1 in cervical cancer. Dual-luciferase reporter assay was used to determine the binding of miR-218 on the IDO1 3′UTR. Cell viability, apoptosis, and related factors were determined using cell counting kit-8 (CCK-8), Annexin-V/PI (propidium) assay, enzyme-linked immunosorbnent assay (ELISA), RT-qPCR, and Western blot assays after miR-218 mimics has been transfected to HeLa cervical cancer cells.ResultsMiR-218 was downregulated in cervical cancer. The expression of miR-218 was negatively correlated with IDO1 in cervical cancer tissues and cells. IDO1 is a direct target of miR-218. MiR-218 overexpression was found to inhibit cell viability and promoted apoptosis via activating the expression of Cleaved-Caspase-3 and to inhibit the expression of Survivin, immune factors (TGF-β, VEGF, IL-6, PGE2, COX-2), and JAK2/STAT3 pathway.ConclusionMiR-218 inhibits immune escape of cervical cancer cells by direct downregulating IDO1.

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Section: Discussionmentioning

confidence: 99%

MiR-218 produces anti-tumor effects on cervical cancer cells in vitro

Zhu¹,

Tu²,

Liang³

et al. 2018

World J Surg Onc

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“…Radiographical response was evaluated by Response Assessment in Neuro-Oncology (RANO) and immunotherapy RANO (iRANO) using gadolinium (Gd) -enhanced T1 weighted images and fluid attenuated IR (FLAIR) on the basis of the appearance of the pretreatment MRI [22,23]. Peptide-specific immunological responses were analyzed by Enzyme-Linked ImmunoSpot (ELISPOT) assay (for details, see the Methods section in Additional file 3) [16,24].…”

Section: Outcomes and Assessmentsmentioning

confidence: 99%

“…Chromosomal number aberrations (CNAs) were assessed by metaphase comparative genomic hybridization, as previously described [25]. Mutation of the isocitrate dehydrogenase (IDH)1 gene, and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation, were also analyzed as previously described [16].…”

Section: Molecular-genetic Analysismentioning

confidence: 99%

“…Peptide vaccination is an immunotherapy that aims to activate cytotoxic T lymphocytes (CTLs) in patients by inoculating antigen peptides. 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].…”

Section: Introductionmentioning

confidence: 99%

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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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“…We have previously conducted exploratory clinical trials investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens (LY6K, DEPDC1, KIF20A, and FOXM1) in patients with primary and recurrent malignant gliomas (UMIN000013381 (jRCTs031180170), UMIN000012774 (jRCTs031180148), and UMIN000005545) [14,22,23]. The inclusion and exclusion criteria were shown in our previous studies [14,22,23]. The Keio University School of Medicine Ethics Committee approved the trials, which were conducted in accordance with the Helsinki declaration on experimentation on human subjects.…”

Section: Methodsmentioning

confidence: 99%

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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A pilot study of peptide vaccines for VEGF receptor 1 and 2 in patients with recurrent/progressive high grade glioma

Cited by 24 publications

References 54 publications

MiR-218 produces anti-tumor effects on cervical cancer cells in vitro

MiR-218 produces anti-tumor effects on cervical cancer cells in vitro

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

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