732 Current Molecular Medicine 2009, 9, 732-739 1566-5240/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. A Review of Studies on Targeting Interleukin 4 Receptor for Central Nervous System Malignancy Sachin Puri* ,#,1,4 , Surbhi Puri 2 , Ashok K. Mahapatra †,3 , Ejaz Hussain 4 , Chitra Sarkar 5 , Subrata Sinha 1 and Bharat H. Joshi 6 1 Department of Biochemistry, All India Institute of Medical Sciences, New Delhi-110029, India; 2 Guru Teg Bahadur Sahib Hospital, Shastri Nagar, Ludhiana-Punjab 141002; 3 Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi-110029, India; 4 Department of Biosciences, Jamia Millia Islamia, New Delhi, India; 5 Department of Pathology, All India Institute of Medical Sciences, New Delhi-110029, India; 6 Tumor Vaccines and Biotechnologies Branch, Division of Cellular, Tissues and Gene Therapies, Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD, USA Abstract: Despite advances in biomedical sciences, the prognosis of patients with brain tumors remains poor. Effective treatment is lacking for these central nervous system (CNS) cancers. Targeted immunotoxins are a new class of therapeutic approaches that have emerged for the treatment of human cancers. In this approach, tumor antigen or cell surface receptor is targeted by a chimeric fusion protein consisting of an antibody or a ligand and a suicidal gene or toxin to kill tumor cells. In that regard, receptors for interleukin (IL)-4 (IL-4R) have been identified to be overexpressed on a variety of human CNS tumor cell lines and tissue samples including meningioma. In various studies, high grade brain tumor specimens and malignant brain tumor cell lines have been shown to overexpress high-affinity IL-4R, while normal brain samples or cell lines expressed lower levels of these receptors. The structures of IL-4R on CNS tumors have been studied, which demonstrate that these cells express predominantly type II IL-4R. These receptors are functional as IL-4 can cause signal transduction, inhibit growth of some tumor cell lines and increase expression of major histocompatibility antigens and intracellular adhesion molecular-1 (ICAM-1) on some tumor cells lines. To target IL-4R, a chimeric fusion protein composed of IL-4 and truncated Pseudomonas exotoxin has been developed. This cytotoxin is highly cytotoxic to IL-4R positive tumors in vitro and has been reported to be highly effective in pre- clinical animal model of human brain cancer. Several Phase I/II clinical trials for treatment of IL-4R positive cancers have been completed. This review article will summarize pre-clinical and clinical development of IL- 4PE cytotoxin. INTRODUCTION Malignant gliomas are the most common type of primary brain tumor, with an annual incidence of approximately five cases per 100,000 people per year [1,2]. Each year, over 15,000 new cases are diagnosed in the United States [3]. Although they are relatively uncommon, they account for a dispropor-tionate amount of cancer-related morbidity and mortality. Glioblastoma multiformes (GBM) account for approximately 60% to 70% of malignant gliomas, anaplastic astrocytomas (AA) account for 10% to 15%, anaplastic oligodendrogliomas (AO) and anaplastic oligoastrocytomas (AOA) account for 10%, and less commonly occurring tumors such as anaplastic epen- dymomas and anaplastic gangliogiomas account for the rest [1, 3, 4]. The incidence of meningiomas ranges *Address correspondence to this author at the Department of Biochemistry, All India Institute of Medical Sciences, New Delhi- 110029, India; E-mail: sachinpuri15@yahoo.com # Present address: Laboratory of Molecular & Tumor Immunology, Earle A. Chiles Research Institute, 4805 NE Glisan Street, 2N123 North Pavilion, Providence Portland Medical Center, Portland, OR 97213, USA. † Present address: Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGI), Raebareli Road Lucknow, India. from as low as 0.3 per 100,000 in childhood to as high as 8.4 per 100,000 in the elderly population [5, 6],with a peak incidence at 45 years of age [7, 8]. Thus, meningiomas account for approximately 15% of all intracranial neoplasms; however, in the pediatric population, they account for 1- 4% of all brain tumors. Despite extensive research, the standard treatment options for GBM tumors remain limited. The median survival of patients with GBM is only 10 to 14 months, whereas that of patients with AA is 2 to 3 years. There is clearly an urgent need to develop newer, more effective therapies to improve patient outcomes. Therapy for GBM is limited to surgery, radiation, and chemotherapy and have been reviewed elsewhere [9- 11]. Although temozolomide (TMZ), an oral alkylating agent, has made a significant impact recently on survival of patients with malignant gliomas, survival remains poor compared with other solid tumors [12, 13]. Over the past several years, a significant progress has been made in the fundamental understanding of the molecular abnormalities in brain tumors, which has allowed for the development of new targeted molecular drugs [14-23]. A variety of cell surface receptors have been identified on brain tumors. A Th2 derived cytokine (IL-