title: Time-dependent transition of the immunoglobulin G subclass and immunoglobulin E response in cancer patients vaccinated with cholesteryl pullulan-melanoma antigen gene-A4 nanogel.
abstract: A phase I+II clinical trial of vaccination with MAGE-A4 protein complexed with cholesteryl pullulan melanoma antigen gene-A4 nanogel (CHP-MAGE-A4) is currently underway in patients with MAGE-A4-expressing cancer. In the present study, the primary phase I endpoint was to test the safety of the administration of 300 µg CHP-MAGE-A4 with and without OK-432. Another aim of the study was to clarify the details of the specific humoral immune response to vaccination. The 9 patients enrolled for phase I were vaccinated 6 times, once every 2 weeks: 3 patients with 100 µg and 3 patients with 300 µg CHP-MAGE-A4, and 3 patients with 300 µg CHP-MAGE-A4 plus 0.5 clinical units of OK-432. Toxicities were assessed using Common Terminology Criteria for Adverse Events v3.0. Clinical response was evaluated by modified Response Evaluation Criteria in Solid Tumours. Immunological monitoring of anti-MAGE-A4-specific antibodies was performed by ELISA of pre- and post-vaccination patient sera. The 6 vaccinations produced no severe adverse events. Stable disease was assessed in 4/9 patients. Anti-MAGE-A4 total immunoglobulin (Ig)G titers increased in 7/9 patients. Efficacious anti-MAGE-A4 IgG1, 2 and 3 antibody responses were observed in 7/9 patients. Among them, positive conversions to T helper 2 (Th2)-type antibody responses (IgG4 and IgE) were observed after frequent vaccination in 4/7 patients. The Th2 conversion was possibly associated with undesirable clinical observations, including progressive disease and the appearance of a new relapse lesion. The present study suggested that frequent vaccinations activated a Th2-dominant status in the cancer patients. The identification of a time-dependent IgG subclass and IgE antibody production during vaccination protocols may be a useful surrogate marker indicating a potentially undesirable change of the immunological environment for an effective antitumor immune response in cancer patients.
authors.affiliation: Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kyogoku
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsuchikawa
authors.affiliation: Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Abiko
authors.affiliation: Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Fujiwara
authors.affiliation: Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Maki
authors.affiliation: Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamamura
authors.affiliation: Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Ichinokawa
authors.affiliation: Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Imai
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyahara
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kageyama
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
authors.affiliation: Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirano
keywords: MAGE-A4; antibody response; immunoglobulin E; immunoglobulin G subclass; vaccine