T cell activation with systemic agonistic antibody versus local 4-1BB ligand gene delivery combined with interleukin-12 eradicate liver metastases of breast cancer.
We have shown that interleukin-12 (IL-12) generated a strong, albeit transient, anti-tumor response, mostly mediated by natural killer (NK) cell. T cell participation, in addition to NK cells, was essential for persistence of the anti-tumor response. Ligation of 4-1BB, a co-stimulatory receptor expressed on activated T cells, is known to amplify T cell-mediated immunity. In this study, we compared the effect of a systemically delivered agonistic anti-4-1BB monoclonal antibody (anti-4-1BB mAb) with intra-tumoral adenoviral-mediated gene transfer of the 4-1BB ligand (ADV/4-1BBL) to liver metastases in a syngeneic animal model of breast cancer. Both treatments induced a dramatic regression of pre-established tumor. When combined with intra-tumoral delivery of the IL-12 gene, both anti-4-1BB mAb and ADV/4-1BBL were synergistic and led to survival rates of 87% and 78%, respectively. The anti-tumor immunity is mainly mediated by CD4+ T cells in IL-12 plus 4-1BB ligand-treated animals, and CD8+ T cells in IL-12 plus anti-4-1BB mAb-treated animals. However, only long-term survivors after treatment with IL-12 and 4-1BBL genes have showed significantly potent, systemic, and tumor-specific T cell-mediated immunity.
Martinet
O
O
Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
Divino
C M
CM
Zang
Y
Y
Gan
Y
Y
Mandeli
J
J
Thung
S
S
Pan
P-Y
PY
Chen
S-H
SH
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007111:Immunity, Cellular; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D017475:Receptors, Nerve Growth Factor / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D018664:Interleukin-12