Abstract
Tumor-directed therapeutic approaches require unique or overexpressed specific Ag or receptor as a target to achieve selective tumor killing. However, heterogeneous expression of these targets on tumor cells limits the efficacy of this form of therapy. In this study, we forced abundant expression of IL-13Ralpha2 chain by plasmid-mediated gene transfer in head and neck, as well as prostate tumors to provide a potential target. This was followed by successfully treating xenograft tumor-bearing nude mice with IL-13R-directed cytotoxin (IL13-PE38QQR). Although we did not observe an indirect cytotoxic bystander effect conveyed to nontransduced tumor cells in vitro, our approach in vivo led to a complete regression of established tumors transfected with IL-13Ralpha2 chain in most animals. We found that the tumor eradication was achieved in part by infiltration of macrophages and NK cells, assessed by immunohistochemistry. Moreover, head and neck tumors xenografted in macrophage-depleted nude mice were less sensitive to the antitumor effect of IL-13 cytotoxin. Because we did not observe vector-related toxicity in any vital organs, our novel combination strategy of gene transfer of IL-13Ralpha2 chain and receptor-directed cytotoxin therapy may be a useful approach for the treatment of localized cancer.
MeSH terms
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Animals
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Antineoplastic Agents / immunology
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Agents / toxicity
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Cytotoxicity, Immunologic / genetics
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Disease Models, Animal
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Exotoxins / genetics
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Exotoxins / therapeutic use*
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Exotoxins / toxicity
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Gene Transfer Techniques*
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Genetic Vectors / administration & dosage
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Genetic Vectors / biosynthesis
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Head and Neck Neoplasms / genetics
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Head and Neck Neoplasms / immunology
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Head and Neck Neoplasms / pathology
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Head and Neck Neoplasms / therapy*
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Humans
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Injections, Intralesional
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Interleukin-13 / genetics
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Interleukin-13 / therapeutic use*
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Interleukin-13 / toxicity
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Interleukin-13 Receptor alpha1 Subunit
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Lymphocytes, Tumor-Infiltrating / pathology
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Macrophages / immunology
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Male
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Mice
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Mice, Nude
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Neoplasm Transplantation
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Phagocytes / immunology*
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Phagocytes / pathology
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Plasmids / administration & dosage
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Plasmids / biosynthesis
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / immunology
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Prostatic Neoplasms / pathology
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Prostatic Neoplasms / therapy*
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Pseudomonas aeruginosa / genetics
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Pseudomonas aeruginosa / immunology*
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Receptors, Interleukin / administration & dosage
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Receptors, Interleukin / biosynthesis
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Receptors, Interleukin / genetics*
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Receptors, Interleukin / therapeutic use
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Receptors, Interleukin-13
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Transfection
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Exotoxins
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IL13RA1 protein, human
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Il13ra1 protein, mouse
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Interleukin-13
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Interleukin-13 Receptor alpha1 Subunit
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Receptors, Interleukin
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Receptors, Interleukin-13
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hIL-13-PE38QQR