IL-13 receptor-targeted cytotoxin cancer therapy leads to complete eradication of tumors with the aid of phagocytic cells in nude mice model of human cancer.
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.
Kawakami
Koji
K
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Kawakami
Mariko
M
Puri
Raj K
RK
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use* / Q000633:toxicity; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004195:Disease Models, Animal; D005098:Exotoxins / Q000235:genetics / Q000627:therapeutic use* / Q000633:toxicity; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000096:biosynthesis; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D015552:Injections, Intralesional; D018793:Interleukin-13 / Q000235:genetics / Q000627:therapeutic use* / Q000633:toxicity; D053661:Interleukin-13 Receptor alpha1 Subunit; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010586:Phagocytes / Q000276:immunology* / Q000473:pathology; D010957:Plasmids / Q000008:administration & dosage / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000276:immunology*; D018123:Receptors, Interleukin / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D053660:Receptors, Interleukin-13; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005098:Exotoxins; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; C451320:hIL-13-PE38QQR