An experimental vaccine expressing wild-type p53 induces protective immunity against glioblastoma cells with high levels of endogenous p53.
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.
Blaszczyk-Thurin
M
M
The Wistar Institute, Philadelphia, PA 19104, USA.
Ertl
I O
IO
Ertl
H C J
HC
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000276:Adjuvants, Immunologic; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage; D007694:Killer Cells, Natural / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D012513:Sarcoma, Experimental / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000637:transplantation; D016159:Tumor Suppressor Protein p53 / Q000008:administration & dosage / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology*; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D007376:Interleukin-2; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D014614:Vaccines, Synthetic