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Updated: Aug 8, 2026
Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts
Published on: September 1, 2018
The IL-4 and IL-13 pseudomonas exotoxins: new hope for brain tumor therapy
Takeshi Shimamura1, Syed R Husain, Raj K Puri
1Tumor 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.
Abstract:
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.
Insights
Researchers developed targeted cytotoxins, IL4-PE and IL13-PE, to treat brain tumors by targeting overexpressed interleukin (IL)-4 and IL-13 receptors on cancer cells. These agents show promise in preclinical and clinical trials for glioma therapy.
Area of Science:
- Oncology
- Molecular Biology
- Neuroscience
Background:
- Interleukin (IL)-4 and IL-13 receptors are overexpressed on various human tumors, including brain tumors.
- Tumor cell cytokine receptor structures differ from normal immune cells, presenting a therapeutic target.
- Targeting these receptors offers a novel approach for brain tumor treatment.
Purpose of the Study:
- To investigate the potential of targeting IL-4 and IL-13 receptors on tumor cells for cancer therapy.
- To develop and evaluate novel recombinant fusion cytotoxins, IL4-PE and IL13-PE, for brain tumor treatment.
Main Methods:
- Generation of recombinant fusion cytotoxins (IL4-PE, IL13-PE) using IL-4 or IL-13 and pseudomonas exotoxin (PE).
- In vitro and in vivo testing of cytotoxin efficacy on human tumor cell lines, primary cultures, and animal models.
- Clinical evaluation of IL13-PE using convection-enhanced delivery (CED) in Phase I/II trials for glioma patients.
Main Results:
- IL4-PE and IL13-PE demonstrated high in vitro and in vivo toxicity against human tumor cells, including gliomas.
- Normal cells, including brain cells, were spared from the cytotoxic effects of the agents.
- Phase I/II trials showed IL13-PE administered via CED was well-tolerated in glioma patients, with a favorable benefit/risk profile.
Conclusions:
- Targeting IL-4 and IL-13 receptors with novel cytotoxins is a promising strategy for brain tumor therapy.
- IL13-PE, delivered via CED, has shown safety and potential efficacy in clinical trials for recurrent glioblastoma multiforme.
- Further clinical trials, including Phase III, are evaluating the long-term outcomes and quality of life for patients treated with IL13-PE.
