Phase I clinical study of multiple epitope peptide vaccine combined with chemoradiation therapy in esophageal cancer patients.
BACKGROUND
Chemoradiation therapy (CRT) has been widely used for unresectable esophageal squamous cell carcinoma (ESCC) patients. However, many patients develop local recurrence after CRT. In this study, we hypothesized that the immunotherapy by peptide vaccine may be effective for the eradication of minimal residual cancer cells after CRT. This study was conducted as a phase I clinical trial of multiple-peptide vaccine therapy combined with CRT on patients with unresectable ESCC.


METHODS
HLA-A*2402 positive 11 unresectable chemo-naïve ESCC patients were treated by HLA-A*2402-restricted multi-peptide vaccine combined with CRT. The peptide vaccine included the 5 peptides as follows; TTK protein kinase (TTK), up-regulated lung cancer 10 (URLC10), insulin-like growth factor-II mRNA binding protein 3 (KOC1), vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2). CRT consisted of radiotherapy (60 Gy) with concurrent cisplatin (40 mg/m²) and 5-fluorouracil (400 mg/m²). Peptide vaccines mixed with incomplete Freund's adjuvant were injected subcutaneously once a week on at least 8 occasions combined with CRT.


RESULTS
Vaccination with CRT therapy was well-tolerated, and no severe adverse effects were observed. In the case of grade 3 toxicities, leucopenia, neutropenia, anemia and thrombocutopenia occurred in 54.5%, 27.3%, 27.3% and 9.1% of patients, respectively. Grade 1 local skin reactions in the injection sites of vaccination were observed in 81.8% of patients. The expressions of HLA class I, URLC10, TTK, KOC1, VEGFR1 and VEGFR2 antigens were observed in the tumor tissues of all patients. All patients showed peptide-specific cytotoxic T lymphocytes responses in at least one of the 5 kinds of peptide antigens during the vaccination. Six cases of complete response (CR) and 5 cases of progressive disease (PD) were observed after the 8th vaccination. The 4 CR patients who continued the peptide vaccination experienced long consistent CR for 2.0, 2.9 4.5 and 4.6 years.


CONCLUSIONS
A combination therapy of multi-peptide vaccine with CRT can successfully be performed with satisfactory levels of safety, and application of this combination therapy may be an effective treatment for patients with unresectable ESCC.


BACKGROUND
ClinicalTrial.gov, number NCT00632333.
Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan. iinuma@med.teikyo-u.ac.jp.
Hisae
H
Iinuma
Ryoji
R
Fukushima
Tsuyoshi
T
Inaba
Junko
J
Tamura
Taisuke
T
Inoue
Etsushi
E
Ogawa
Masahiro
M
Horikawa
Yoshibumi
Y
Ikeda
Noriyuki
N
Matsutani
Kazuyoshi
K
Takeda
Koji
K
Yoshida
Takuya
T
Tsunoda
Tadashi
T
Ikeda
Yusuke
Y
Nakamura
Kota
K
Okinaga
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D019496:Cancer Vaccines; D000939:Epitopes; D010455:Peptides; D002945:Cisplatin; D005472:Fluorouracil