title: Phase I trial of OTS11101, an anti-angiogenic vaccine targeting vascular endothelial growth factor receptor 1 in solid tumor.
abstract: OTS11101 is a novel peptide vaccine that acts as an angiogenesis inhibitor by inducing cytotoxic T lymphocyte (CTL) cells that specifically target vascular endothelial cells expressing vascular endothelial growth factor (VEGF) receptor 1. We conducted a phase I study to evaluate the safety, tolerability, maximum tolerated dose, and pharmacodynamic biomarker status of this vaccine. Nine patients with advanced solid tumors received 1.0, 2.0, or 3.0 mg of OTS11101 subcutaneously, once a week in a 28-day cycle. Three patients experienced grade 1 injection site reactions, which were the most frequent adverse events. Grade 2 proteinuria and hypertension each occurred in one patient. As other toxicities were generally mild, the maximum tolerated dose was not reached. Furthermore, we explored the induction of specific activated CTLs, and biomarkers related to angiogenesis. A pharmacodynamics study revealed that induction of specific CTLs was observed for a dose of 2.0 and 3.0 mg. The serum concentrations of soluble VEGF receptor 1 and 2 after vaccination increased significantly compared with baseline. A microarray was performed to give a comprehensive analysis of gene expression, suggesting that OTS11101 vaccination resulted in T cell activation in a clinical setting. In conclusion, OTS11101 was well tolerated in patients up to 3.0 mg once weekly and our biomarker analysis suggested that this anti-angiogenesis vaccine is biologically active.
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Takayasu
authors.initials: T
authors.lastname: Kurata
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujisaka
authors.forename: Hisato
authors.initials: H
authors.lastname: Kawakami
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tanaka
authors.forename: Takafumi
authors.initials: T
authors.lastname: Okabe
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
authors.forename: Taroh
authors.initials: T
authors.lastname: Satoh
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshida
authors.forename: Takuya
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Tokuzo
authors.initials: T
authors.lastname: Arao
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D059871:HLA-A24 Antigen / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood*
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D022223:Vaccines, Subunit; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2