Clinical and immunological evaluation of anti-apoptosis protein, survivin-derived peptide vaccine in phase I clinical study for patients with advanced or recurrent breast cancer.
BACKGROUND
We previously reported that survivin-2B, a splicing variant of survivin, was expressed in various types of tumors and that survivin-2B peptide might serve as a potent immunogenic cancer vaccine. The objective of this study was to examine the toxicity of and to clinically and immunologically evaluate survivin-2B peptide in a phase I clinical study for patients with advanced or recurrent breast cancer.


METHODS
We set up two protocols. In the first protocol, 10 patients were vaccinated with escalating doses (0.1-1.0 mg) of survivin-2B peptide alone 4 times every 2 weeks. In the second protocol, 4 patients were vaccinated with the peptide at a dose of 1.0 mg mixed with IFA 4 times every 2 weeks.


RESULTS
In the first protocol, no adverse events were observed during or after vaccination. In the second protocol, two patients had induration at the injection site. One patient had general malaise (grade 1), and another had general malaise (grade 1) and fever (grade 1). Peptide vaccination was well tolerated in all patients. In the first protocol, tumor marker levels increased in 8 patients, slightly decreased in 1 patient and were within the normal range during this clinical trial in 1 patient. With regard to tumor size, two patients were considered to have stable disease (SD). Immunologically, in 3 of the 10 patients (30%), an increase of the peptide-specific CTL frequency was detected. In the second protocol, an increase of the peptide-specific CTL frequency was detected in all 4 patients (100%), although there were no significant beneficial clinical responses. ELISPOT assay showed peptide-specific IFN-gamma responses in 2 patients in whom the peptide-specific CTL frequency in tetramer staining also was increased in both protocols.


CONCLUSIONS
This phase I clinical study revealed that survivin-2B peptide vaccination was well tolerated. The vaccination with survivin-2B peptide mixed with IFA increased the frequency of peptide-specific CTL more effectively than vaccination with the peptide alone, although neither vaccination could induce efficient clinical responses. Considering the above, the addition of another effectual adjuvant such as a cytokine, heat shock protein, etc. to the vaccination with survivin-2B peptide mixed with IFA might induce improved immunological and clinical responses.
Tsuruma
Tetsuhiro
T
Dept. of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan. tsuruma@sapmed.ac.jp
Iwayama
Yuji
Y
Ohmura
Tosei
T
Katsuramaki
Tadashi
T
Hata
Fumitake
F
Furuhata
Tomohisa
T
Yamaguchi
Koji
K
Kimura
Yasutoshi
Y
Torigoe
Toshihiko
T
Toyota
Nobuhiko
N
Yagihashi
Atsuhito
A
Hirohashi
Yoshihiko
Y
Asanuma
Hiroko
H
Shimozawa
Kumiko
K
Okazaki
Minoru
M
Mizushima
Yasuhiro
Y
Nomura
Naohiro
N
Sato
Noriyuki
N
Hirata
Koichi
K
D000328:Adult; D000368:Aged; D000917:Antibody Formation / Q000502:physiology; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002277:Carcinoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D005260:Female; D006801:Humans; D007167:Immunotherapy; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000276:immunology*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D012008:Recurrence; D012698:Serologic Tests; D000077022:Survivin
C107489:BIRC5 protein, human; D019496:Cancer Vaccines; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D000077022:Survivin