Tumor growth and metastasis rely on angiogenesis and lymphangiogenesis triggered by chemical signals from tumor cells in a phase of rapid growth. In a previous study, it was demonstrated that cancer cells only grew to less than 2 mm in diameter without blood circulation, but grew more than 2mm when placed in an area where angiogenesis was possible[1]. In the absence of vascular support, tumors may become necrotic or even apoptotic. Therefore, angiogenesis is an important factor in the progression of cancer.
Angiogenesis is regulated by both activator and inhibitor molecules, it results from up-regulation of the activity of angiogenesis factors and down-regulation of inhibitors of vessel growth. More than a dozen different factors have been identified as angiogenesis activators, among them; vascular endothelial growth factor (VEGF) family and their receptors (VEGFR) are receiving most attention in the field of neoplastic vascularization. VEGF is a powerful angiogenic agent in neoplastic tissues, as well as in normal tissues. Under the influence of certain cytokines and other growth factors, the VEGF family and their receptors appear in cancerous tissue and the adjacent stroma. Additionally, they play an important role in neovascularization. The binding of VEGF to its receptor activates relay proteins that transmit a signal into the nucleus of the endothelial cell. The nuclear signal prompts a group of genes to make products needed for new endothelial cell growth and new vessel formation to support tumor progression.
There are several different types of targeted therapy. The most common types are monoclonal antibodies or small-molecule drugs. The identification of novel angiogenic therapeutic targets and development of novel drugs as alternative or combination treatments with existing drugs are needed to improve the survival and quality of life of cancer patients.Therapeutic immunotherapies targeting tumor angiogenesis[2] have been developed (see Figure 1). In particular, four antibody drugs have been approved by FDA for clinical use to block tumor angiogenesis, Avastin (targeting VEGF), Zaltrap (VEGF and PGF), Cyramza (VEGFR2) and Lartruvo (PDGFRa).
Figure 1. Mechanisms of action of monoclonal antibodies targeting VEGF, PDGF, HGF, Ang, their receptors for suppressing tumor growth and angiogenesis.
In recent years, due to massively-parallel sequencing for detection of all coding mutations with tumors, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules, personalized peptide neoantigen vaccinations became feasible. Vaccination with neoantigen can both expand pre-existing neoantigen-specific T cell populations and induce a broader repertoire of new T cell specificities in cancer patients, alone or in combination with other available cancer therapy such as check point inhibitors to control tumor growth and cause regression.
A number of early stage clinical studies have demonstrated the feasibility of peptide vaccines targeting VEGF receptor 1 and 2 (VEGFR1 and 2) in patients with high grade glioma. VEGFR1 and 2 are induced in a tumor stage-dependent manner during glioma progression and are exclusively expressed in tumor vascular endothelial cells and glioma cells, VEGF receptors are promising targets for tumor endothelial cell specific therapy for glioma patients. Shibao S et al[3] reported an eight-patient study using two peptide vaccines, one peptide from VEGFR1(VEGFR1-1084) and another one from VEGFR2 (VEGFR2-169). : Eight patients received vaccinations weekly at a dose of 2mg/kg bodyweight 8 times. The treatment was well-tolerated in patients. The first four vaccines induced positive immune responses against at least one of the targeted VEGFR epitopes in 87.5% of patients. The median overall survival time in all patients was 15.9 months. Two achieved progression-free status lasting at least 6 months. Two patients with recurrent GBM demonstrated stable disease. Plasma IL-8 level was negatively correlated with overall survival. These data demonstrate the safety and immunogenicity of VEGFR peptide vaccines targeting tumor vasculatures in high grade gliomas.
Kikuchi R et al [4]reported a combination vaccination of angiogenesis-associated antigen peptides (VEGFR1-1084 and VEGFR2-169) with multiple glioma neoantigen peptides in 10 patients with high-grade glioma, The treatment was well tolerated without any severe systemic adverse events. The vaccinations induced immunoreactivity to at least three vaccine-targeted multiple glioma neoantigen and angiogenesis-associated antigen peptides in all six evaluable patients. The median overall survival time in all patients was 9.2 months. Five achieved progression-free status lasting at least six months. Two recurrent glioblastoma patients demonstrated stable disease. One patient with anaplastic oligoastrocytoma achieved complete response nine months after the vaccination. Taken together, this regimen was well tolerated and induced robust peptide antigen-specific T-lymphocyte responses in recurrent/progressive HGG patients.
Peptide vaccines targeting angiogenesis factor VEGFR1 and 2 can be combined with standard therapies such chemotherapy and targeted small molecule drugs. More than one dozen clinical studies are ongoing to evaluate the synergistic effects of VEGFR1 and VEGR2 peptide vaccine combined with standard therapies to treat patients with solid tumors. Hopefully these studies will provide proof of concept for therapeutic vaccine targeting tumor angiogenesis rather than biomarkers of tumor as biomarkers can be easily mutated and cause immune escape.
Written By Feng Lin, MD, PhD, Scientist
Keywords: Tumors, VEGF, peptide vaccines, glioma
References:
1 Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag 2006; 2: 213-219 [PMID: PMC1993983 DOI: 10.2147/vhrm.2006.2.3.213]
2 Kong DH, Kim MR, Jang JH, Na HJ, Lee S. A review of anti-angiogenic targets for monoclonal antibody cancer therapy. Int J Mol Sci 2017; 18: [PMID: PMC5578174 DOI: 10.3390/ijms18081786]
3 Shibao S, Ueda R, Saito K, Kikuchi R, Nagashima H, Kojima A, Kagami H, Pareira ES, Sasaki H, Noji S, Kawakami Y, Yoshida K, Toda M. A pilot study of peptide vaccines for vegf receptor 1 and 2 in patients with recurrent/progressive high grade glioma. Oncotarget 2018; 9: 21569-21579 [PMID: PMC5940381 DOI: 10.18632/oncotarget.25131]
4 Kikuchi R, Ueda R, Saito K, Shibao S, Nagashima H, Tamura R, Morimoto Y, Sasaki H, Noji S, Kawakami Y, Yoshida K, Toda M. A pilot study of vaccine therapy with multiple glioma oncoantigen/glioma angiogenesis-associated antigen peptides for patients with recurrent/progressive high-grade glioma. J Clin Med 2019; 8: [PMID: PMC6406695 DOI: 10.3390/jcm8020263]