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.