Rejection of disseminated metastases of colon carcinoma by synergism of IL-12 gene therapy and 4-1BB costimulation.
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.
Chen
S H
SH
Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. chens01@doc.mssm.edu
Pham-Nguyen
K B
KB
Martinet
O
O
Huang
Y
Y
Yang
W
W
Thung
S N
SN
Chen
L
L
Mittler
R
R
Woo
S L
SL
D053330:4-1BB Ligand; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013997:Time Factors; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053330:4-1BB Ligand; D015703:Antigens, CD; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12