CpG oligodeoxynucleotides as immunotherapy in cancer.
CpG oligodeoxynucleotides as immunotherapy in cancer.
复制标题
DOI：
10.1016/j.uct.2007.11.003
复制
发表时间：
2008-03-01
期刊：
影响因子：
--
通讯作者：
Weiner, George J
中科院分区：
文献类型：
--
作者：
Jahrsdorfer, Bernd;Weiner, George J
临床前和早期临床试验表明，含非甲基化CG二核苷酸的人工合成寡脱氧核苷酸（CpG ODN）具有很强的免疫刺激作用，可增强多种癌症治疗的抗癌活性。CpG ODN和单克隆抗体之间的协同作用已经在各种临床前模型中被注意到。早期临床试验表明，CpG ODN和单克隆抗体可以安全地一起施用。临床前模型表明，CpG ODN可以增强化疗和放疗的抗肿瘤活性。因此，使用CpG ODN的一种可能的方法是将其与细胞毒性化疗联合使用，目的是增强垂死癌细胞对肿瘤抗原的呈递。在非小细胞肺癌患者中进行的随机II期试验的结果令人鼓舞，导致启动了两项大型随机III期试验，比较CpG ODN联合化疗与单独化疗。不幸的是，这些试验的中期分析表明CpG ODN不太可能增强化疗的疗效，因此停止了这些试验。CpG ODN也有望作为癌症疫苗的组分，包括由蛋白抗原、肽、全肿瘤细胞和抗原脉冲树突状细胞组成的那些。最后，CpG ODN已与多种细胞因子组合以增强NK活化，促进主动抗肿瘤免疫应答的发展或诱导表达TLR9受体的恶性细胞的凋亡。总体而言，临床前和早期临床试验均表明CpG ODN可能是多种癌症治疗方法的有价值的组成部分。然而，这种最近发现的新型免疫刺激剂的临床开发才刚刚开始，我们仍然需要了解它们的最佳使用方法及其潜力。
Preclinical and early clinical trials indicate synthetic oligodeoxynucleotides containing unmethylated CG dinucleotides (CpG ODN) have potent immunostimulatory effects and can enhance the anti-cancer activity of a variety of cancer treatments. Synergy between CpG ODN and monoclonal antibodies has been noted in various preclinical models. Early clinical trials indicate CpG ODN and monoclonal antibodies can be administered safely together. Preclinical models indicate CpG ODN can enhance the anti-tumor activity of both chemotherapy and radiation therapy. Thus, one possible approach to the use of CpG ODN was to use it in combination with cytotoxic chemotherapy with the goal of enhancing presentation of tumor antigen from dying cancer cells. Promising results in a randomized phase II trial in patients with non-small cell lung cancer led to initiation of two large randomized phase III trials comparing CpG ODN plus chemotherapy to chemotherapy alone. Unfortunately, interim analysis of these trials indicated CpG ODN was unlikely to enhance efficacy of chemotherapy, and they were stopped. CpG ODN also holds promise as a component of cancer vaccines including those composed of protein antigen, peptides, whole tumor cells, and antigen-pulsed dendritic cells. Finally, CpG ODN has been combined with a variety of cytokines to enhance NK activation, promote development of an active anti-tumor immune response or induce apoptosis of malignant cells that express the TLR9 receptor. Overall, both preclinical and early clinical trials suggest CpG ODN may be a valuable component of a variety of approaches to cancer therapy. However, clinical development of this recently discovered, novel class of immunostimulatory agents is just beginning, and we still have much to learn about the optimal approach to their use, and their potential.