Impact of p53-based immunization on primary chemically-induced tumors.

Abstract:

:In mice as well as humans, cytotoxic T lymphocytes (CTL) specific for wild-type-sequence (wt) p53 peptides have been shown to react against a wide range of tumors, but not normal cells. As such, they are attractive candidates for developing broadly applicable cancer vaccines. Of particular interest is the potential of using p53-based vaccines in high-risk individuals to prevent cancer. Methylcholanthrene, an immunosuppressive polycyclic hydrocarbon carcinogen implicated as a causative agent in human cancers, has long been used to induce murine tumors with a high incidence of genetic alterations and sensitivity to wt p53-specific CTL. To analyze the potential of p53-based vaccines on primary tumors, we evaluated the efficacy of DNA and dendritic cell vaccines targeting wt p53 peptides given to methylcholanthrene-treated mice in the protection or therapy settings. The results indicate that the efficacy of these vaccines relative to reducing tumor incidence were severely compromised by vaccine-induced tumor escape. As compared to tumors induced in non-immunized mice, a higher incidence of epitope-loss tumors was detected in tumors from the immunized mice. The increase in tumor escape arose as a consequence of either increased frequencies of mutations within/flanking p53 epitope-coding regions or downregulation of expression of the major histocompatibility complex Class I molecules that present these epitopes for T cell recognition These findings are consistent with current views of immunoselection occurring in patients receiving tumor peptide-based immunotherapy, and impact on the design and implementation of p53-based vaccines, in particular, those aimed at treating individuals at high risk for developing cancer.

journal_name

Int J Cancer

authors

Cicinnati VR,Dworacki G,Albers A,Beckebaum S,Tüting T,Kaczmarek E,DeLeo AB

doi

10.1002/ijc.20686

keywords:

subject

Has Abstract

pub_date

2005-03-01 00:00:00

pages

961-70

issue

6

eissn

0020-7136

issn

1097-0215

journal_volume

113

pub_type

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