Metronomic Chemotherapy Enhances Antitumor Effects of Cancer Vaccine by Depleting Regulatory T Lymphocytes and Inhibiting Tumor Angiogenesis
Metronomic Chemotherapy Enhances Antitumor Effects of Cancer Vaccine by Depleting Regulatory T Lymphocytes and Inhibiting Tumor Angiogenesis
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DOI：
10.1038/mt.2010.34
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发表时间：
2010-06-01
影响因子：
12.4
通讯作者：
Cheng, Wen-Fang
中科院分区：
文献类型：
--
作者：
Chen, Chi-An;Ho, Chih-Ming;Cheng, Wen-Fang
尽管癌症疫苗正在作为癌症治疗的创新方法出现，但这些疫苗本身在治疗可测量的肿瘤负担方面的潜力有限。因此，确定更有效的抗癌策略的重要性是必要的。嵌合DNA疫苗CTGF/E7(与肿瘤抗原人乳头瘤病毒16E7相连的结缔组织生长因子)产生强大的E7特异性免疫和抗肿瘤作用。我们测试了免疫调节剂化疗与CTGF/E7 DNA疫苗联合治疗小鼠现有肿瘤的效果。节律性的低剂量紫杉醇，而不是最大耐受量，与抗原特异性DNA疫苗具有协同作用。紫杉醇与CTGF/E7 DNA疫苗一起按节拍顺序给予，比单独使用CTGF/E7 DNA疫苗更能增强疫苗延缓肿瘤生长和减少体内转移肿瘤的潜力。节律性紫杉醇化疗的两种可能机制是耗尽调节性T细胞和抑制肿瘤血管生成，而不是直接杀伤癌细胞。结果表明，节律化疗与抗原特异性DNA疫苗联合治疗能诱导更强的抗原特异性免疫应答和抗肿瘤效应。这为癌症患者的进一步检测提供了免疫学基础。
Although cancer vaccines are emerging as innovative methods for cancer treatment, these alone have limited potential for treating measurable tumor burden. Thus, the importance of identifying anticancer strategies with greater potency is necessary. The chimeric DNA vaccine CTGF/E7 (connective tissue growth factor linked to the tumor antigen human papillomavirus 16 E7) generates potent E7-specific immunity and antitumor effects. We tested immune-modulating doses of chemotherapy in combination with the CTGF/E7 DNA vaccine to treat existing tumors in mice. Metronomic low doses of paclitaxel, not the maximal tolerable dose, are synergistic with the antigen-specific DNA vaccine. Paclitaxel, given in metronomic sequence with the CTGF/E7 DNA vaccine enhanced the vaccine's potential to delay tumor growth and decreased metastatic tumors in vivo better than the CTGF/E7 DNA vaccine alone. The two possible mechanisms of metronomic paclitaxel chemotherapy are the depletion of regulatory T cells and the inhibition of tumor angiogenesis rather than direct cancer cell cytolytic effects. Results indicate that combination treatment of metronomic chemotherapy and antigen-specific DNA vaccine can induce more potent antigen-specific immune responses and antitumor effects. This provides an immunologic basis for further testing in cancer patients.