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

Abstract

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.

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

“…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.…”

“…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.…”

“…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 ].…”

Monitoring T Cells Responses Mounted by Therapeutic Cancer Vaccines

“…The use of MAGE-A3 peptide vaccine as cancer therapeutic agent has resulted in a big disappointment as no significant clinical benefit was observed in two Phase III clinical trials (MAGRIT and DERMA) for patients with non-small cell lung cancer and melanoma ( Vansteenkiste et al, 2016 ; Dreno et al, 2018 ). To circumvent the lack of response to peptide vaccine, new studies are designed to target more than one antigen to avoid the risk for tumor escape due to antigen loss and to combine these vaccines with other approved therapies, for example, chemotherapy and checkpoint blockade inhibitors ( Kanekiyo et al, 2018 ; Kawamura et al, 2018 ; Noguchi et al, 2020 ; Tamura et al, 2020 ). The use of RNF43/TOMM3 peptide vaccine in combination with chemotherapy in metastatic colorectal cancer has demonstrated significantly better 3-year relapse-free survival in patients who have higher T cell responses compared to the negative response subgroup ( Kawamura et al, 2018 ).…”

Antiangiogenic Targets for Glioblastoma Therapy from a Pre-Clinical Approach, Using Nanoformulations

“…When the tumor grows to a thickness of more than 2 mm, the cells in the nucleus are farther away from the blood supply, and the exposure of cancer cells to certain hypoxic stimuli [ 9 , 11 ] is the main trigger for initiating a series of reactions involving diverse molecular processes; for example, expression of hypoxia-inducible factors (HIF) that stimulate the expression of vascular endothelial growth factors (VEGFs) by tumor cells [ 8 , 9 , 12 ], in addition to communication with its auxiliary cells that stimulate the formation of other growth factors, such as platelet-derived growth factors (PDGFs) [ 12 , 13 , 14 , 15 ] and epidermal growth factors (EGFs) [ 10 , 16 , 17 ]. In chemotactic communication, inflammatory cells are recruited, such as tumor-associated macrophages (TAMs), which, in turn, stimulate a chain reaction of continuous tumor growth, intensifying the signaling of hypoxia to tumor cells, which further stimulates the expression of HIF and, mainly, VEGF [ 18 , 19 , 20 , 21 , 22 ].…”