Abstract
Inoculation of mice with a recombinant vaccinia virus expressing the full-length mouse wild-type p53 protein (Vp53-wt) was shown to induce partial protection against peripheral challenge with a mouse glioblastoma cell line, termed GL261, expressing high levels of nuclear, endogenous wild-type p53. In vivo experiments with knockout (KO) mice and mice treated with depleting doses of antibodies specific to lymphocyte subsets revealed that vaccine efficacy depended on CD4+ and CD8+ T cells as well as on natural killer (NK) cells. Vp53-wt virus-vaccinated mice that failed to develop tumours upon challenge with a minimal tumourigenic dose of GL261 cells remained completely resistant to further challenge with increased doses of GL261 cells. The efficacy of the Vp53-wt vaccine was improved by adding recombinant mouse interleukin-12 (rIL-12) as an adjuvant at the time of tumour challenge. The induction of T cells to p53 in Vp53-wt virus-immune mice was also demonstrated at the tumour site by immunochemistry and was further confirmed by a delayed-type hypersensitivity response to the p53 protein, although in vitro experiments using splenocytes from vaccinated mice failed to demonstrate CD4+ or CD8+ T-cell activity to p53.
MeSH terms
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Adjuvants, Immunologic
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Animals
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CD4-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / immunology
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Cancer Vaccines / immunology*
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Female
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Gene Expression Regulation, Neoplastic
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Genes, p53
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Glioblastoma / immunology
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Glioblastoma / prevention & control*
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Hypersensitivity, Delayed / immunology
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Interleukin-2 / administration & dosage
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Killer Cells, Natural / immunology
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Lymphocytes, Tumor-Infiltrating / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Recombinant Fusion Proteins / administration & dosage
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Sarcoma, Experimental / metabolism
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Sarcoma, Experimental / pathology
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Tumor Cells, Cultured / transplantation
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Tumor Suppressor Protein p53 / administration & dosage
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Tumor Suppressor Protein p53 / biosynthesis
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / immunology*
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Vaccination
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Vaccines, Synthetic / immunology
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Vaccinia virus / genetics
Substances
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Adjuvants, Immunologic
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Cancer Vaccines
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Interleukin-2
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Neoplasm Proteins
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Recombinant Fusion Proteins
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Tumor Suppressor Protein p53
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Vaccines, Synthetic