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Cancer Immunology, Immunotherapy

, Volume 67, Issue 9, pp 1371–1380 | Cite as

Immunotherapy with cancer peptides in combination with intravesical bacillus Calmette–Guerin for patients with non-muscle invasive bladder cancer

  • Wataru ObaraEmail author
  • Isao Hara
  • Yoichiro Kato
  • Renpei Kato
  • Keiji Inoue
  • Fuminori Sato
  • Hiromitsu Mimata
  • Yusuke Nakamura
  • Tomoaki Fujioka
Original Article

Abstract

Purpose

A phase I study using two peptide vaccines derived from M phase phosphoprotein 1 (MPHOSPH1) and DEP domain containing 1 (DEPDC1) demonstrated promising results for the treatment of advanced bladder cancer. Therefore, we further tested the ability of these peptides to prevent recurrence after transurethral resection of the bladder tumor in patients with non-muscle invasive bladder cancer (NMIBC).

Materials and methods

127 patients were enrolled in a multicenter, non-randomized phase II clinical trial. The primary endpoint was recurrence-free survival (RFS) rate, and secondary endpoints were safety and immunological response. HLA-A24-restricted peptides were subcutaneously administered in addition to intravesical BCG therapy. The exploratory endpoint evaluated differences of RFS rate between HLA-A*2402-positive (A24(+)) and -negative (A24(−)) groups.

Results

A 2-year RFS rate in all patients was 74.0%. The RFS rate in the A24(+) group (n = 75) and in the A24(−) group (n = 52) were 76.0 and 71.2%, respectively. This vaccine therapy was well-tolerated and feasible. MPHOSPH1 and DEPDC1 peptide-specific cytotoxic T lymphocyte responses were observed in 75.8 and 77.5% of the A24(+) group, respectively. Patients having both peptide-specific CTL responses showed significantly better RFS than patients without CTL response (P = 0.014). In the A24(+) group, patients who had positive reaction at the injection sites (RAI) had significantly lower rates of recurrence than RAI-negative patients (P = 0.0019).

Conclusions

Cancer peptide vaccines in combination with intravesical BCG therapy demonstrated good immunogenicity and safety, and may provide benefit for preventing recurrence of NMIBC.

Keywords

Cancer peptide vaccine Adjuvant therapy Non-muscle invasive bladder cancer M phase phosphoprotein 1 DEP domain containing 1 

Abbreviations

APC

Antigen-presenting cells

BCG

Bacillus Calmette–Guérin

CTL

Cytotoxic T lymphocyte

DEPDC1

DEP domain containing 1

ELISPOT

Enzyme-linked immunospot

EORTC

European Organization for Research and Treatment of Cancer

HLA

Human leukocyte antigen

MPHOSPH1

M phase phosphoprotein 1

NMIBC

Non-muscle invasive bladder cancer

PBLs

Peripheral blood lymphocytes

PD-1

Programmed death-1

PD-L1

Programmed death-ligand 1

RAIs

Reaction at the injection sites

RFS

Recurrence-free survival

TURBT

Trans-urethral resection of the bladder tumor

UC

Urothelial cancer

Notes

Acknowledgements

We thank Dr. Keiichi Tozawa and Dr. Kenjiro Kohri (Nagoya City University), Dr. Kazuya Mikami and Dr. Tsuneharu Miki (Kyoto Prefectural University of Medicine), Dr. Takashi Kasrashima and Dr. Taro Shuin (Kochi Medical School), Dr. Naoki Mitsuhata (Kure-Kyosai Hospital), Dr. Mitsuo Nishi (Saint Martin’s Hospital), Dr. Yoshihide Ogawa (Tokyo-West Tokushukai Hospital), Dr. Hisaaki Afuso (Nambu Tokushukai Hospital), Dr. Takahito Nasu (Tokuyama Central Hospital), and Dr. Ichiro Miura (Shonan Kamakura General Hospital) for case enrollment. We also thank Dr. Koji Yoshida and Dr. Takuya Tsunoda for providing all of the peptides. We thank Reiko Shinagawa for technical assistance.

Author contributions

Clinical trial was designed by WO, YN and TF; patient registrations were provided by WO, YK, RK, KI, FS and HM; data analysis was done by IH; the manuscript was written by WO and YN and was reviewed by all co-authors.

Compliance with ethical standards

Conflict of interest

Y. Nakamura reports receiving a commercial research grant from and has ownership interest (including patents) in OncoTherapy Science, Inc. No potential conflicts of interest were disclosed by the other authors.

Ethical approval

This study was approved by the institutional review board at each hospital and was registered with Clinical Trials.gov as NCT 00633204. This study was carried out according to the Helsinki declaration on experimentation on human subjects.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of UrologyIwate Medical University School of MedicineMoriokaJapan
  2. 2.Department of UrologyWakayama Medical UniversityWakayamaJapan
  3. 3.Department of UrologyKochi Medical SchoolNankokuJapan
  4. 4.Department of Urology, Faculty of MedicineOita UniversityYufuJapan
  5. 5.Section of Hematology/Oncology, Department of MedicineThe University of ChicagoChicagoUSA

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