IL-12 and mutant P53 peptide-pulsed dendritic cells for the specific immunotherapy of cancer.
Mice bearing palpable tumors expressing a mutant p53 gene were treated with intravenous injection of mutant p53-specific peptide-pulsed dendritic cells (DCs). Control groups were treated with control peptide-pulsed DCs. All mice received three injections of 10(5) DCs on days 0, 5, and 10 after the start of the therapy. Half of the animals in each group were also treated with intraperitoneal injections of interleukin (IL)-12 (300 ng per mouse every other day, from day 0 to day 20). Mice treated with control peptide-pulsed DCs showed fast tumor progression. This growth was not substantially affected by treatment with IL-12 alone. Tumor growth in mice treated with mutant p53 peptide-pulsed DCs was significantly slowed during therapy, but resumed after cessation of therapy. In contrast, tumor growth in mice receiving both specific peptide-pulsed DCs and IL-12 remained very slow even 4 weeks after termination of the immunotherapy. To investigate the immunological basis for these effects, mutant p53 specific cytotoxic T lymphocyte (CTL) response was tested in mice 2 weeks after the last injection of DCs. Significant levels of CTLs were registered only in mice treated with IL-12 in addition to specific immunization. Thus, IL-12 dramatically improved the effect of the mutant p53-specific immunotherapy of palpable, preexisting tumors, supporting the use of IL-12 as an immunoadjuvant in clinical trials of tumor-specific peptide-pulsed DC.
Gabrilovich
D I
DI
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, USA.
Cunningham
H T
HT
Carbone
D P
DP
D000595:Amino Acid Sequence; D000818:Animals; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000637:transplantation*; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007275:Injections, Intravenous; D018664:Interleukin-12 / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D010455:Peptides / Q000235:genetics* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000627:therapeutic use*
D010455:Peptides; D016159:Tumor Suppressor Protein p53; D018664:Interleukin-12