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Prospect of Targeting the CD40 Pathway for Cancer Therapy

Author's Affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Robert H. Vonderheide, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 551 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104. Phone: 215-573-4265; Fax: 215-573-2652; E-mail: rhv{at}mail.med.upenn.edu.

The cell surface molecule CD40 is a member of the tumor necrosis factor receptor superfamily and is broadly expressed by immune, hematopoietic, vascular, epithelial, and other cells, including a wide range of tumor cells. CD40 itself lacks intrinsic kinase or other signal transduction activity but rather mediates its diverse effects via an intricate series of downstream adapter molecules that differentially alter gene expression depending on cell type and microenvironment. As a potential target for novel cancer therapy, CD40 may mediate tumor regression through both an indirect effect of immune activation and a direct cytotoxic effect on the tumor, resulting in a "two-for-one" mechanism of action of CD40 agonists. Several drug formulations that target the CD40 pathway have undergone phase 1 clinical evaluation in advanced-stage cancer patients, and initial findings show objective clinical responses and immune modulation in the absence of major toxicity.

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