A Pilot Study of Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma

Kikuchi, Ryogo; Ueda, Ryo; Saito, Kei; Shibao, Shunsuke; Nagashima, Hideaki; Tamura, Ryota; Morimoto, Yukina; Sasaki, Hidenao; Noji, Shinobu; Kawakami, Yutaka; Yoshida, Kazunari; Toda, Masahiro

doi:10.3390/jcm8020263

Cited by 25 publications

(11 citation statements)

References 44 publications

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“…Clinical trials of peptide-based vaccine therapy using VEGFR-derived epitopes have previously been conducted to assess safety, tolerability, and potential clinical activity in patients with advanced pancreas, gastrointestinal, and renal cell cancers (see Supplementary Table 3) 21–28 . In addition, we previously conducted exploratory clinical trials investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens in patients with recurrent high-grade gliomas, wherein treatment exhibited safety and yielded therapeutic effects in some patients 8,29 . In one clinical trial using only VEGFRs peptide vaccination in patients with recurrent high-grade glioma, eight patients received weekly vaccinations for 8 weeks.…”

Section: Discussionmentioning

confidence: 99%

A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2

et al. 2019

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The anti-VEGF antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Theoretically, vascular endothelial growth factor receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. Here we show an exploratory clinical study of VEGFRs peptide vaccine in seven patients with progressive NF2-derived schwannomas. Hearing improves in 2/5 assessable patients (40%) as determined by international guidelines, with increases in word recognition scores. Tumor volume reductions of ≥20% are observed in two patients, including one in which bevacizumab had not been effective. There are no severe adverse events related to the vaccine. Both VEGFR1-specific and VEGFR2-specific CTLs are induced in six patients. Surgery is performed after vaccination in two patients, and significant reductions in the expression of VEGFRs in schwannomas are observed. Therefore, this clinical immunotherapy study demonstrates the safety and preliminary efficacy of VEGFRs peptide vaccination in patients with NF2.

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Section: Discussionmentioning

confidence: 99%

A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2

et al. 2019

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“…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%

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%

“…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%

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 Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma

Cited by 25 publications

References 44 publications

A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2

A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2

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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