The aim of this study is to develop an immunization regimen based on vaccine expressing wild-type p53 for the eventual treatment of human cancer. The applicant has already shown that mouse wild-type p53 encoded by a recombinant vaccinia virus induces a protective immune response to some mouse tumors that express high levels of endogenous p53. The applicant's hypothesis is that over-expression of wild-type p53 by the vaccine exposes so called cryptic epitopes that can induce a T cell response which in turn, assisted by the innate immune system, limits the growth of tumor cells expressing high levels of p53. The applicant proposes to extend these studies using a DNA vaccine encoding a biologically inactive form of a p53 fusion protein that, by addition of a signal sequence, is targeted towards the endosomal pathway for ready association of epitopic peptides with major histocompatibility complex (MHC) determinants. In the first aim, the applicant will test this DNA vaccine for induction of antigen specific immune responses, as well as for protection to a subsequent tumor challenge. The efficacy of the vaccine will be optimized by applying cytokines in the form of genetic adjuvants as well as by prime-boost vaccine regimens using the DNA vaccine for priming and viral recombinants for booster immunization. The effect of the pre-existing tumors on vaccine-induced stimulation of an immune response to p53 will be investigated. In the second aim, the applicant will test the hypothesis that the immune response to p53 is directed to cryptic epitopes of the protein by comparing the T cell epitope profile of p53+ mice to those of p53- mice. In addition, the applicant will determine the immune effector mechanisms that contribute to the elimination of tumor cells using mice lacking lymphocyte subsets or cytokines due to introduced germ-line defects or upon antibody-mediated depletion. In the third aim, the applicant's studies will be extended to additional tumor models. The optimized DNA vaccine will be tested for induction of protective immunity to challenge with these tumor cell lines that all express high levels of p53; tumor characteristics that reduce the efficacy of the vaccine will be elucidated.
| Insug, O; Ku, Geoffrey; Ertl, Hildegund C J et al. (2002) A dendritic cell vaccine induces protective immunity to intracranial growth of glioma. Anticancer Res 22:613-21 |
