The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma.
We have previously shown that the local-membrane bound 4-1BB ligand and IL-12 gene transfer induced a significant antitumor response in a mouse colon carcinoma model. However, a high viral dose was required in order to achieve the best efficacy. In this study, we hypothesize that the systemic administration of soluble Ig-4-1BB ligand can give rise to better T-cell immune activation than local gene delivery. With potential clinical applications in mind, we further compare whether the natural 4-1BB ligand fused to mouse IgG2a (Ig-4-1BBL) would be as effective as the agonistic anti-4-1BB antibody. The dimeric form of Ig-4-1BBL was purified from HeLa cells transduced with a recombinant adenovirus (ADV/Ig-4-1BBL) expressing Ig-4-1BBL. Functional activity was confirmed by the ligand's ability to bind to activated splenic T cells or bone marrow (BM)-derived dendritic cells (DCs) that express 4-1BB receptor. The soluble Ig-4-1BBL efficiently costimulated CD3-activated T-cell proliferation in vitro. More importantly, it induced tumor-specific CTLs as effectively as the agonistic anti-4-1BB antibody. When combined with IL-12 gene transfer, systemic administration of the Ig-4-1BBL proved to be more potent than local gene delivery. In addition, the Ig-4-1BBL is as potent as the agonistic anti-4-1BB antibody for the treatment of hepatic MCA26 colon carcinoma, resulting in 50% complete tumor regression and long-term survival. In long-term surviving mice, both treatment modalities induced persistent tumor-specific CTL activity. In summary, these results suggest that the systemic delivery of Ig-4-1BBL can generate a better antitumor response than local gene delivery. Ig-4-1BBL had equivalent biological functions when compared to the agonistic anti-4-1BB antibody. Thus, soluble 4-1BBL dimmer can be developed as a promising agent for cancer therapy in humans.
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, NY 10029, USA.
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D053330:4-1BB Ligand; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D007074:Immunoglobulin G / Q000235:genetics*; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008113:Liver Neoplasms / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic / Q000379:methods; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000276:immunology
D053330:4-1BB Ligand; D000906:Antibodies; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; C505975:Tnfsf9 protein, mouse; D048069:Tumor Necrosis Factors; D018664:Interleukin-12