Cancer Immunology, Immunotherapy

, Volume 65, Issue 2, pp 151–160 | Cite as

A randomized phase II clinical trial of personalized peptide vaccination with metronomic low-dose cyclophosphamide in patients with metastatic castration-resistant prostate cancer

  • Masanori Noguchi
  • Fukuko Moriya
  • Noriko Koga
  • Satoko Matsueda
  • Tetsuro Sasada
  • Akira Yamada
  • Tatsuyuki Kakuma
  • Kyogo Itoh
Original Article


This study investigated the effect of metronomic cyclophosphamide (CPA) in combination with personalized peptide vaccination (PPV) on regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), and whether it could improve the antitumor effect of PPV. Seventy patients with metastatic castration-resistant prostate cancer were randomly assigned (1:1) to receive PPV plus oral low-dose CPA (50 mg/day), or PPV alone. PPV treatment used a maximum of four peptides chosen from 31 pooled peptides according to human leukocyte antigen types and antigen-specific humoral immune responses before PPV, for 8 subcutaneous weekly injections. Peptide-specific cytotoxic T lymphocyte (CTL) and immunoglobulin G responses were measured before and after PPV. The incidence of grade 3 or 4 hematologic adverse events was higher in the PPV plus CPA arm than in the PPV alone arm. Decrease in Treg and increase in MDSC were more pronounced in PPV plus CPA treatment than in PPV alone (p = 0.036 and p = 0.048, respectively). There was no correlation between the changes in Treg or MDSC and CTL response. There was no difference in positive immune responses between the two arms, although overall survival in patients with positive immune responses was longer than in those with negative immune responses (p = 0.001). Significant differences in neither progression-free survival nor overall survival were observed between the two arms. Low-dose CPA showed no change in the antitumor effect of PPV, possibly due to the simultaneous decrease in Treg and increase in MDSC, in patients under PPV.


Peptide vaccination Cyclophosphamide Regulatory T cell Myeloid-derived suppressor cell Immunotherapy Phase II trial 





Androgen deprivation therapy


Adverse events




Castration-resistant prostate cancer


Computed tomography


Cytotoxic T lymphocytes


Eastern Cooperative Oncology Group


Fetal bovine serum


Fluorescence intensity units


Human leukocyte antigen


Hazard ratio




Immunoglobulin G




Metastatic castration-resistant prostate cancer


Myeloid-derived suppressor cells


Overall survival


Peripheral blood mononuclear cells


Phosphate-buffered solution


Progressive disease


Progression-free survival


Personalized peptide vaccine


Performance status


Prostate-specific antigen


Tumor-associated antigen


Regulatory T cells



This study was supported in part by Grants-in-Aid (KAKENHI) (No. 22591782 to Masanori Noguchi) of the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Compliance with ethical standards

Conflict of interest

Noguchi M has served as an advisory board consultant for Green Peptide Co. Ltd. Itoh K has served as a consultant and received research funding from Taiho Pharmaceutical Company. Yamada A is a part-time executive of Green Peptide Co. Ltd. and has stock in this company. Moriya F, Koga N, Matsueda S, Sasada T, and Kakuma T declare no competing interests.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Masanori Noguchi
    • 1
    • 2
    • 4
  • Fukuko Moriya
    • 3
  • Noriko Koga
    • 1
  • Satoko Matsueda
    • 4
  • Tetsuro Sasada
    • 5
  • Akira Yamada
    • 6
  • Tatsuyuki Kakuma
    • 7
  • Kyogo Itoh
    • 4
  1. 1.Division of Clinical Research, Research Center for Innovative Cancer TherapyKurume University School of MedicineKurumeJapan
  2. 2.Department of UrologyKurume University School of MedicineKurumeJapan
  3. 3.Department of PathologyKurume University School of MedicineKurumeJapan
  4. 4.Cancer Vaccine CenterKurume University School of MedicineKurumeJapan
  5. 5.Kanagawa Cancer Center Research InstituteYokohamaJapan
  6. 6.Division of Cancer Vaccines, Research Center for Innovative Cancer TherapyKurume University School of MedicineKurumeJapan
  7. 7.Bio-statistics CenterKurume University School of MedicineKurumeJapan

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