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Published Data on IL13-PE38 Identifies Mechanism of Drug Action for The Treatment of Malignant Glioma
Intratumoral Administration of IL13-PE38 Induces Apoptotic Cell Death in Human Malignant Glioma Tumor Xenografts
Nov. 7, 2002
In a series of laboratory experiments designed to help define the molecular mechanisms for the therapeutic properties of the drug IL13-PE38, the authors identified that human glioma (brain) tumor cells that express the IL-13 receptor undergo programmed cell death, or apoptosis, following intratumoral administration of IL13-PE38, leading to regression of established tumors. IL13-PE38 appears to be tumor-selective and induces apoptosis, which persists after the drug is no longer detectable. These findings shed light on the molecular pathways of inducing apoptosis in malignant glioma tumors and subsequent tumor regression mediated by this receptor-targeted cytotoxin and will provide insights assessing IL13-PE38 tumor response and developing the optimal clinical regimen for treatment of malignant glioma.
"These data published by Dr. Puri and his group further support the potential of IL13-PE38 as a tumor selective agent for the treatment of malignant glioma, a dreadful and devastating disease," said James M. Hussey, President and CEO, NeoPharm, Inc. NeoPharm is currently conducting Phase I/II clinical trials for IL13-PE38 and has scheduled a meeting with the FDA in December to determine the requirements to begin Phase II/III clinical trials.
Background Information
The Mechanism of IL13-PE38 Compared with Standard Chemotherapy Malignant glioma cells, as compared to normal brain cells, express interleukin-13 (IL13) receptors at a high density. IL13 is an immune regulatory cytokine, or protein, secreted by cells. IL13-PE38 (a recombinant protein) is designed to detect and bind to IL13 receptors on the surface of malignant glioma cancer cells. It then selectively delivers a potent bacterial cytotoxic agent called PE38, derived from Pseudomonas bacterium to destroy tumor cells while sparing healthy surrounding cells. In contrast, conventional, non-specific chemotherapeutic drugs attack abnormal cancer cells by stopping them from dividing and reproducing, but can also damage normal cells because these agents are not selective for just cancer cells and are almost always administered systemically. This means that the systemic medicines are diffused throughout the body rather than being localized to one area, such as a tumor in the brain, and cannot discriminate between cancer and healthy cells. Common chemotherapy side effects occur when bone marrow is damaged and cannot produce enough red blood cells (causing weakness and fatigue), white blood cells (lowering the body´s resistance to infections) or platelets (preventing blood from clotting properly, which can lead to excessive bleeding).
IL13-PE38, on the other hand, is being developed as a highly specific tumor-targeting agent. It is administered directly to the tumor through positive-pressure convection enhanced delivery (CED), which uses catheters inserted in the brain before and/or following surgical resection (removal) of the tumor. CED is designed to infuse IL13-PE38 directly to the tumor site and adjacent brain tissue to prevent recurrence of tumor cell growth. Investigators have sought to identify the optimum "therapeutic window" to provide patients with the safest, most effective dose levels at sufficient toxic concentrations to kill tumor cells while minimizing toxic exposure to healthy tissues.
Phase I/II IL13-PE38 Clinical Program
IL13-PE38 is currently under investigation in three ongoing Phase I/II clinical trials. The first IL13-PE38 clinical study is being conducted through the NCI Clinical Trial Evaluation Program (CTEP)-funded New Approaches to Brain Tumor Therapy (NABTT) Consortium. Johns Hopkins University Medical Center is the coordinating site for NABTT. The first human clinical data on IL13-PE38 from this study was presented last Fall at the Sixth Annual Meeting of the World Federation of Neuro-Oncology/Society for Neuro-Oncology (SNO). These data indicated that IL13-PE38 might have potential as a safe and effective treatment for malignant glioma. Noticeable response to IL13-PE38 was observed in two of six patients in the NABTT study at the initial dose level. One patient, who was treated with IL13-PE38, subsequently underwent surgical removal of the tumor mass. A histopathologic evaluation following surgery found IL13-PE38 effective in destroying approximately 95 percent of the malignant tumor cells. In a second patient, following IL13-PE38 administration, radiographic scans of the brain revealed a significant reduction and disappearance in the size of the tumor, and the patient did not require a scheduled, additional, IL13-PE38 infusion. More recent findings will be presented at the upcoming Seventh Annual Meeting of the World Federation of Neuro-Oncology/Society for Neuro-Oncology (SNO) in San Diego on November 24th, 2002.
The second clinical study includes M.D. Andersen Cancer Center (MDACC), Memorial Sloan Kettering Cancer Center (MSKCC), the University of California San Francisco (UCSF) and Yale University as participating centers. Additional preliminary clinical data was recently presented at the Fifth Congress of the European Association of Neuro-Oncology (EANO).
In addition, enrollment has begun in the first global Phase I/II clinical trial of IL13-PE38; the third NeoPharm sponsored clinical study to date in patients with recurrent or progressive malignant glioma. The trial is being conducted at six participating sites including University Hospital Eppendorf and University Hospital Kiel in Germany, Chaim Sheba Medical Center and Dana Hospital Tel Aviv in Israel, Cleveland Clinic and University of Colorado in the United States. The trial´s first cohort of three patients was enrolled in the first month of the study and enrollment is ongoing in the second cohort of patients.