title: A randomized phase II trial of personalized peptide vaccine with low dose cyclophosphamide in biliary tract cancer.
abstract: Since the prognosis of advanced biliary tract cancer (aBTC) still remains very poor, new therapeutic approaches, including immunotherapies, need to be developed. In the current study, we conducted an open-label randomized phase II study to test whether low dose cyclophosphamide (CPA) could improve antigen-specific immune responses and clinical efficacy of personalized peptide vaccination (PPV) in 49 previously treated aBTC patients. Patients with aBTC refractory to at least one regimen of chemotherapies were randomly assigned to receive PPV with low dose CPA (100 mg/day for 7 days before vaccination) (PPV/CPA, n = 24) or PPV alone (n = 25). A maximum of four HLA-matched peptides were selected based on the pre-existing peptide-specific IgG responses, followed by subcutaneous administration. T cell responses to the vaccinated peptides in the PPV/CPA arm tended to be greater than those in the PPV alone arm. The PPV/CPA arm showed significantly better progression-free survival (median time: 6.1 vs 2.9 months; hazard ratio (HR): 0.427; P = 0.008) and overall survival (median time: 12.1 vs 5.9 months; HR: 0.376; P = 0.004), compared to the PPV alone arm. The PPV alone arm, but not the PPV/CPA arm, showed significant increase in plasma IL-6 after vaccinations, which might be associated with inhibition of antigen-specific T cell responses. These results suggested that combined treatment with low dose CPA could provide clinical benefits in aBTC patients under PPV, possibly through prevention of IL-6-mediated immune suppression. Further clinical studies would be recommended to clarify the clinical efficacy of PPV/CPA in aBTC patients.
authors.affiliation: Department of Surgery, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Shirahama
authors.affiliation: Department of Surgery, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Muroya
authors.affiliation: Cancer Vaccine Center, Kurume University, Kurume, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsueda
authors.affiliation: Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Cancer Vaccine Center, Kurume University, Kurume, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shichijo
authors.affiliation: Cancer Vaccine Center, Kurume University, Kurume, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Naito
authors.affiliation: Department of Biostatistics Center, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Takuto
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.|Department of Molecular and Internal Medicine School of Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Shinjiro
authors.identifier: http://orcid.org/0000-0002-2805-900X
authors.initials: S
authors.lastname: Sakamoto
authors.affiliation: Department of Surgery, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Okuda
authors.affiliation: Cancer Vaccine Center, Kurume University, Kurume, Japan.
authors.forename: Kyogo
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Cancer Vaccine Center, Kurume University, Kurume, Japan.|Cancer Vaccine Center, Kanagawa Cancer Center, Yokohama, Japan.
authors.forename: Tetsuro
authors.identifier: http://orcid.org/0000-0002-2313-8833
authors.initials: T
authors.lastname: Sasada
authors.affiliation: Cancer Vaccine Center, Kurume University, Kurume, Japan.
authors.forename: Shigeru
authors.identifier: http://orcid.org/0000-0001-6306-4130
authors.initials: S
authors.lastname: Yutani
mesh_terms: D000368:Aged; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000627:therapeutic use*; D057285:Precision Medicine / Q000379:methods; D014611:Vaccination / Q000379:methods
chemical_list: D019496:Cancer Vaccines; D015850:Interleukin-6; D010455:Peptides; D003520:Cyclophosphamide
keywords: Biliary tract cancer; IL-6; cyclophosphamide; peptide vaccine; randomized phase II clinical trial