Rejection of disseminated metastases of colon carcinoma by synergism of IL-12 gene therapy and 4-1BB costimulation.
Mol Ther
; 2(1): 39-46, 2000 Jul.
Article
em En
| MEDLINE
| ID: mdl-10899826
ABSTRACT
In an orthotopic model of metastatic colon carcinoma established in the liver of mice, we have previously shown that the natural killer (NK) cells were the major effectors after intratumoral delivery of a recombinant adenovirus expressing the murine IL-12 gene. However, tumor cure and long-term survival were achieved only in a minority of animals. In the present study, we generated an effective antitumoral CD8(+ ) T-cell response by the combination of IL-12 gene therapy and systemic delivery of an agonistic monoclonal antibody against 4-1BB, a costimulatory molecule expressed on activated T cells. In the IL-12 plus anti-4-1BB combination treatment, the effective dose of IL-12 could even be reduced even up to 18-fold and still achieved a better efficacy than the maximal dose of either treatment alone. We further demonstrate that the innate and the adaptive antitumoral immune responses were synergistic, as animals bearing hepatic as well as multiple pulmonary metastases were quantitatively cured of their diseases after IL-12 gene therapy + anti-4-1BB combination treatment. Both NK and CD8(+) T cells were necessary in maintaining the long-term antitumor immunity, as depletion of either cell type in the cured animals abolished their abilities to reject tumor cells implanted at distal sites. These results indicate that synergism between innate and adaptive immune responses may be effectively exploited to treat patients with metastatic diseases.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
/
Receptores de Fator de Crescimento Neural
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Receptores do Fator de Necrose Tumoral
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Neoplasias do Colo
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Interleucina-12
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Metástase Neoplásica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Mol Ther
Ano de publicação:
2000
Tipo de documento:
Article