Garnett Charlie T, Schlom Jeffrey, Hodge James W
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Clin Cancer Res. 2008 Jun 1;14(11):3536-44. doi: 10.1158/1078-0432.CCR-07-4025.
Taxanes comprise some of the most widely used cancer chemotherapeutic agents. Members of this drug family, including docetaxel, are commonly used to treat breast, prostate, and lung cancers, among others. This study was designed to determine if this taxane has the ability to modulate components of the immune system independent of antitumor activity and to investigate the potential synergistic activities of the combination of docetaxel and vaccine therapy.
We examined the in vivo effects of docetaxel on immune-cell subsets and on the function of CD4+, CD8+, and regulatory T-cell (Treg) populations in response to antigen-specific vaccination. We also examined the antitumor effects of the combination of docetaxel and vaccine in a preclinical model in which docetaxel has no observable effect on tumor growth.
These studies show for the first time that (a) docetaxel modulates CD4+, CD8+, CD19+, natural killer cell, and Treg populations in non-tumor-bearing mice; (b) unlike cyclophosphamide, docetaxel does not inhibit the function of Tregs; (c) docetaxel enhances CD8+ but not CD4+ response to CD3 cross-linking; (d) docetaxel given after vaccination provides optimal enhancement of immune response to recombinant viral vaccines; (e) docetaxel combined with recombinant viral vaccine is superior to either agent alone at reducing tumor burden; and (f) docetaxel plus vaccine increases antigen-specific T-cell responses to antigen in the vaccine, as well as to cascade antigens derived from the tumor.
These findings suggest potential clinical benefit for the combined use of docetaxel and recombinant cancer vaccines.
紫杉烷类是一些应用最为广泛的癌症化疗药物。该药物家族的成员，包括多西他赛，常用于治疗乳腺癌、前列腺癌和肺癌等多种癌症。本研究旨在确定这种紫杉烷是否具有独立于抗肿瘤活性之外调节免疫系统成分的能力，并探究多西他赛与疫苗疗法联合使用的潜在协同活性。
我们研究了多西他赛在体内对抗免疫细胞亚群以及对抗CD4 +、CD8 +和调节性T细胞（Treg）群体功能的影响，这些细胞群体是针对抗原特异性疫苗接种产生的反应。我们还在一个临床前模型中研究了多西他赛与疫苗联合使用的抗肿瘤效果，在该模型中多西他赛对肿瘤生长没有明显影响。
这些研究首次表明：（a）多西他赛可调节未荷瘤小鼠体内的CD4 +、CD8 +、CD19 +、自然杀伤细胞和Treg群体；（b）与环磷酰胺不同，多西他赛不会抑制Treg的功能；（c）多西他赛可增强CD8 +细胞对CD3交联的反应，但不会增强CD4 +细胞的反应；（d）接种疫苗后给予多西他赛可最佳增强对重组病毒疫苗的免疫反应；（e）多西他赛与重组病毒疫苗联合使用在减轻肿瘤负担方面优于单独使用任何一种药物；（f）多西他赛加疫苗可增加对抗疫苗中抗原以及肿瘤衍生级联抗原的抗原特异性T细胞反应。
这些发现表明多西他赛与重组癌症疫苗联合使用可能具有临床益处。
