Immunomodulatory gene therapy with interleukin 12 and 4-1BB ligand: long- term remission of liver metastases in a mouse model.
BACKGROUND
The success of immunomodulatory cancer therapy is frequently hampered by the transient nature of the antitumor immune response. We have shown previously in a mouse model that interleukin 12 (IL-12) generates a strong natural killer (NK) cell-mediated antitumor response and reduces liver metastases induced by a colon carcinoma cell line. However, only a small percentage of the treated animals developed the cytotoxic T-lymphocytic response required for a long-term systemic antitumor immunity. 4-1BB is a co-stimulatory molecule expressed on the surface of activated T cells. Interaction of 4-1BB with its natural ligand (4-1BBL) has been shown to amplify T-cell (especially CD8+)-mediated immunity. In this study, we investigated the effects of adenovirus-mediated gene therapy delivering both IL-12 and 4-1BBL genes on mice with hepatic metastases induced by colon cancer cells.


METHODS
Syngeneic BALB/c mice received intrahepatic injection of poorly immunogenic MCA26 colon cancer cells. Various combinations of replication-defective adenoviruses expressing IL-12 and 4-1BBL genes were injected into the established liver tumors. Changes in tumor size and animal survival were then monitored. All statistical tests were two-sided.


RESULTS
The long-term survival rate of mice treated with the combination of IL-12 and 4-1BBL was significantly improved over that of animals in the control group (P =.0001). In vivo depletion of NK cells or CD8+ T cells completely abolished the long-term survival advantage of the IL-12 plus 4-1BBL-treated animals (P<.002). Moreover, the systemic immunity induced by this combination treatment protected these animals against a subcutaneous challenge with parental MCA26 cells.


CONCLUSIONS
Adenovirus-mediated transfer of IL-12 and 4-1BBL genes directly into liver tumors resulted in tumor regression that required both NK and CD8+ T cells and generated a potent, long-lasting antitumor immunity.
Martinet
O
O
Institute for Gene Therapy and Molecular Medicine, The Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
Ermekova
V
V
Qiao
J Q
JQ
Sauter
B
B
Mandeli
J
J
Chen
L
L
Chen
S H
SH
D053330:4-1BB Ligand; D000256:Adenoviridae; D000276:Adjuvants, Immunologic / Q000235:genetics / Q000627:therapeutic use*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003110:Colonic Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018664:Interleukin-12 / Q000235:genetics / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology*; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000627:therapeutic use*
D053330:4-1BB Ligand; D000276:Adjuvants, Immunologic; C505975:Tnfsf9 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12