Immunotherapy with cancer peptides in combination with intravesical bacillus Calmette–Guerin for patients with non-muscle invasive bladder cancer
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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.
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).
Cancer peptide vaccines in combination with intravesical BCG therapy demonstrated good immunogenicity and safety, and may provide benefit for preventing recurrence of NMIBC.
KeywordsCancer peptide vaccine Adjuvant therapy Non-muscle invasive bladder cancer M phase phosphoprotein 1 DEP domain containing 1
Cytotoxic T lymphocyte
DEP domain containing 1
European Organization for Research and Treatment of Cancer
Human leukocyte antigen
M phase phosphoprotein 1
Non-muscle invasive bladder cancer
Peripheral blood lymphocytes
Programmed death-ligand 1
Reaction at the injection sites
Trans-urethral resection of the bladder tumor
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.
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.
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 was obtained from all individual participants included in the study.
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