Rationale for Antiangiogenic Cancer Therapy with Vaccination Using Epitope Peptides Derived from Human Vascular Endothelial Growth Factor Receptor 2

Abstract

Angiogenesis is a critical mechanism for tumor progression. Multiple studies have suggested that tumor growth can be suppressed if tumor angiogenesis can be inhibited using various types of antiangiogenic agents. Recent studies in mouse systems have shown that tumor angiogenesis can also be inhibited if cellular immune response could be induced against vascular endothelial growth factor receptor 2 (VEGFR2), which is one of the key factors in tumor angiogenesis. In this study, we examined the possibility of developing this novel immunotherapy in clinical setting. We first identified the epitope peptides of VEGFR2 and showed that stimulation using these peptides induces CTLs with potent cytotoxicity in the HLA class I-restricted fashion against not only peptidepulsed target cells but also endothelial cells endogenously expressing VEGFR2. In A2/Kb transgenic mice that express A1 and A2 domains of human HLA-A*0201, vaccination using these epitope peptides in vivo was associated with significant suppression of the tumor growth and prolongation of the animal survival without fatal adverse effects. In antiangiogenesis assay, tumor-induced angiogenesis was significantly suppressed with the vaccination using these epitope peptides. Furthermore, CTLs specific to the epitope peptides were successfully induced in cancer patients, and the specificities of the CTLs were confirmed using functional and HLA-tetramer analysis. These results in vitro and in vivo strongly suggest that the epitope peptides derived from VEGFR2 could be used as the agents for antiangiogenic immunotherapy against cancer in clinical settings. (Cancer Res 2005; 65(11): 4939-46)

A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate?

“…17,35,37 Several studies suggested that targeting VEGFR2 may elicit and improve the immune response directed toward the tumor and its microenvironment trough different mechanisms including direct activation of CD8 C cells and targeting of the FOXP3 high regulatory T cells. [87][88][89][90][91][92][93][94][95] These findings could explain, at least in part, the efficacy of ramucirumab, a mAb IgG1 direct to VEGFR2 and appear of interest taking also into account that GC is a disease in which VEGFR2 expression has not been reported to retain a prognostic weight. 96 Moreover, recent evidence underscored the prognostic roles of both VEGFA and VEGFC expression in GC.…”

Clinical Application of Drug Delivery Systems for Treating AMD

“…VEGFR2 vaccination therapy has been progressed in the cancer field (Niethammer et al, 2002, Wada et al, 2005, Pan et al, 2008. The strategy of VEGFR vaccination therapy for wet AMD is to induce apoptosis of neovascular endothelial cells, and inhibition and regression of CNV by cytotoxic T lymphocytes (CTLs).…”

“…Takahashi et al have demonstrated that vaccination with human VEGFR2-derived epitope peptide (VEGFR2-773) significantly inhibited CNV in laser-induced A2/Kb transgenic mice, which express chimeric humanmouse MHC class I molecule, and this chimeric molecule shows 71% concordance with the human CTL repertoire (Vitiello et al, 1991). VEGFR2 peptide induces CTLs in the histocompatibility leukocyte antigen (HLA) class I-restricted manner (Wada et al, 2005).…”

Inhibition of angiogenesis by a Semliki Forest virus vector expressing VEGFR-2 reduces tumour growth and metastasis in mice

“…Although recently most preclinical studies have focused on the induction of T-cell responses to VEGFR-2 as a means to target tumour angiogenesis, 17,18,20,21,34,35 antibody-based therapies have proved to be clinically effective for the treatment of metastatic cancer. Bevacizumab (Avastin) is a monoclonal antibody specific for VEGF and has recently been approved by the FDA for treatment of patients with metastatic colorectal cancer.…”

“…One of the most successful of these Bevacizumab (Avastin, Genentech, San Francisco, CA, USA) has shown improved survival of patients with metastatic colorectal cancer in a phase III study. 15 Recently, several preclinical studies have shown that active immunization with purified xenogenic VEGFR-2, 16 dendritic cells (DC) pulsed with autologous VEGFR-2 protein/peptides, 17,18 DC transfected with VEGFR-2 mRNA 19 or vaccination with attenuated Salmonella typhimurium carrying VEGFR-2 cDNA 20,21 can break immunological tolerance to VEGFR-2 leading to inhibition of tumour growth and metastasis.…”