The IL-4 and IL-13 pseudomonas exotoxins: new hope for brain tumor therapy.
Targeting cell surface receptors with cytotoxins or immunotoxins provides a unique opportunity for brain tumor therapy. The authors have discovered that receptors for two cytokines, interleukin (IL)-4 and IL-13, are overexpressed on tumor biopsy samples and on cell lines derived from a variety of human tumors, including brain tumors. These investigators have demonstrated that the structure of these cytokine receptors on tumor cells is different from that found on normal immune cells. In human solid tumor cells, IL-4 binds to two chains (IL-4Ra and IL-13Ra1), whereas IL- 13 binds to three chains in many solid tumor cells, including glioma cells (to IL-4Ra, IL-13Ra1, and IL-13Ra2). To target IL-4Rs and IL-13Rs, the authors generated two recombinant fusion cytotoxins composed of IL-4 or IL-13 and a mutated form of pseudomonas exotoxin (PE), which for simplicity are called IL4-PE and IL13-PE in this paper. These chimeric cytotoxins are highly toxic in vitro to human tumor cell lines and primary cell cultures, including glioma cells, and in vivo to animal models of human tumors, including gliomas. In contrast, normal cells, including immune, endothelial, and brain cells, are spared from their cytotoxic effects. Based on numerous preclinical studies, IL13-PE (also known as IL13-PE38QQR or cintredekin besudotox) has been tested in four Phase I/II clinical trials. The agent IL13-PE was administered intracranially by using convection-enhanced delivery (CED). The drug was delivered through catheters placed either directly into the tumor bed or in the peritumoral region after resection of the lesion. The CED of IL13-PE was fairly well tolerated, with a reasonable benefit/risk profile for treatment of patients with glioma. Based on Phase I/II clinical trials, the Phase III Randomized Evaluation of CED of IL13-PE Compared to Gliadel Wafer with Survival Endpoint Trial (also known as the PRECISE Trial) in patients with initial recurrence of glioblastoma multiforme has recently been completed. Patients are being monitored for safety of the agents, duration of overall survival, and quality of life.
Shimamura
Takeshi
T
Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, Maryland 20892, USA.
Husain
Syed R
SR
Puri
Raj K
RK
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy*; D005098:Exotoxins / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000633:toxicity; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D018793:Interleukin-13 / Q000737:chemistry*; D015847:Interleukin-4 / Q000737:chemistry*; D018123:Receptors, Interleukin / Q000187:drug effects / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000633:toxicity
D000970:Antineoplastic Agents; D005098:Exotoxins; D000922:Immunotoxins; D018793:Interleukin-13; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4