Vonderheide Robert H
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Clin Cancer Res. 2007 Feb 15;13(4):1083-8. doi: 10.1158/1078-0432.CCR-06-1893.
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.
细胞表面分子CD40是肿瘤坏死因子受体超家族的成员，广泛表达于免疫细胞、造血细胞、血管细胞、上皮细胞及其他细胞，包括多种肿瘤细胞。CD40本身缺乏内在激酶或其他信号转导活性，而是通过一系列复杂的下游衔接分子介导其多种效应，这些衔接分子根据细胞类型和微环境差异地改变基因表达。作为新型癌症治疗的潜在靶点，CD40可能通过免疫激活的间接效应和对肿瘤的直接细胞毒性效应介导肿瘤消退，从而产生CD40激动剂的“一举两得”作用机制。几种靶向CD40通路的药物制剂已在晚期癌症患者中进行了1期临床评估，初步结果显示出客观的临床反应和免疫调节，且无重大毒性。
