Metronomic chemotherapy enhances antitumor effects of cancer vaccine by depleting regulatory T lymphocytes and inhibiting tumor angiogenesis.
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.
Chen
Chi-An
CA
Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan.
Ho
Chih-Ming
CM
Chang
Ming-Cheng
MC
Sun
Wei-Zun
WZ
Chen
Yu-Li
YL
Chiang
Ying-Cheng
YC
Syu
Ming-Hong
MH
Hsieh
Chang-Yao
CY
Cheng
Wen-Fang
WF
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D019496:Cancer Vaccines; D006801:Humans; D008212:Lymphocyte Depletion; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000628:therapy*; D009389:Neovascularization, Pathologic; D017239:Paclitaxel / Q000008:administration & dosage; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D017239:Paclitaxel