Induction of p53-specific immune responses in colorectal cancer patients receiving a recombinant ALVAC-p53 candidate vaccine.
OBJECTIVE
The tumor-associated auto-antigen p53 is commonly overexpressed in various types of human cancer, including colorectal cancer. Experiments in preclinical models have shown that it can serve as a target for T-cell-mediated tumor-eradication. The feasibility of a p53-specific therapeutic vaccination was investigated in cancer patients.


METHODS
A Phase I/II dose-escalation study was performed that evaluated the effect of a recombinant canarypoxvirus (ALVAC) vaccine encoding wild-type human p53 in 15 patients with advanced colorectal cancer. Each group of five patients received three i.v. doses of one-tenth of a dose, one-third of a dose, or 1 dose of the vaccine [1 dose = 1 x 10(7.5) cell culture infectious dosis (CCID)50].


RESULTS
Potent T-cell and IgG antibody responses against the vector component of the ALVAC vaccine were induced in the majority of the patients. Enzyme-linked immunosorbent-spot assay (ELISPOT) analysis of vaccine-induced immunity revealed the presence of IFN-gamma-secreting T cells against both ALVAC and p53, whereas no significant interleukin-4 responses were detected. Vaccine-mediated enhancement of p53-specific T-cell immunity was found in two patients in the highest-vaccine-dose group.


CONCLUSIONS
This study demonstrated the feasibility, even in patients with advanced cancer, to elicit immune responses against the ubiquitously expressed tumor-associated auto-antigen p53. Our results form the basis for additional studies that will explore the antitumor capacity of p53 containing multivalent vaccines in cancer patients with limited tumor burden.
van der Burg
Sjoerd H
SH
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, the Netherlands. shvdburg@worldonline.nl
Menon
Anand G
AG
Redeker
Anke
A
Bonnet
Marie-Claude
MC
Drijfhout
Jan Wouter
JW
Tollenaar
Rob A E M
RA
van de Velde
Cornelis J H
CJ
Moingeon
Philippe
P
Kuppen
Peter J K
PJ
Offringa
Rienk
R
Melief
Cornelis J M
CJ
D000328:Adult; D000368:Aged; D000917:Antibody Formation; D028121:Canarypox virus / Q000235:genetics; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000187:drug effects; D007075:Immunoglobulin M / Q000097:blood / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D014611:Vaccination
D019496:Cancer Vaccines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53