Vaccine and Drug Combination Therapy for Human Cancers

表达肿瘤相关抗原（TAAs）的重组痘病毒目前正在临床试验中作为一种治疗各种癌症的方法进行评估。我们之前已经生成了表达TAA和三组协同刺激分子（B7-1， ICAM-1和LFA-3；指定为TRICOM）作为转基因的痘病毒载体，包括复制能力强的重组痘苗（rV）或复制缺陷修饰的安卡拉痘苗（MVA），以引发肿瘤特异性免疫反应，以及复制缺陷的重组鸡痘（rF）以增强这些反应。MVA是一种潜在更安全的、具有复制缺陷的牛痘病毒形式，具有独特的免疫刺激特性，使其成为一种优越的启动疫苗。本研究利用MVA载体编码肿瘤抗原（CEA）和TRICOM （rMVA）。与牛痘相比，单次接种rMVA-CEA/TRICOM疫苗诱导了与增强t细胞免疫相关的几种血清细胞因子的更多表达。我们假设这种效应可能是疫苗接种部位更有效增强的先决条件。7天后（而不是30天后），rMVA-CEA/TRICOM在同一注射部位（而不是远端部位）增强rF-CEA/TRICOM，诱导了更强的cea特异性t细胞反应，并具有更好的cea特异性免疫和抗肿瘤活性，而不是rV-CEA/TRICOM再加rF-CEA/TRICOM。在异种抗原模型中也观察到这种预处理效应，与仅使用rF-LacZ/TRICOM相比，用rMVA-CEA/TRICOM引发7天后，rF-LacZ/TRICOM增强了β - goal特异性免疫。这些研究首次表明，与远端注射部位相比，在同一注射部位注入rMVA并在7天后进行rF增强，可产生更好的肿瘤特异性免疫和抗肿瘤活性。多西紫杉醇联合重组疫苗增强t细胞应答和抗肿瘤活性：多西紫杉醇对免疫增强的影响。紫杉烷包括一些最广泛使用的癌症化疗药物。该药物家族的成员，包括多西他赛，通常用于治疗乳腺癌、前列腺癌和肺癌等。本研究旨在确定这种紫杉烷是否具有独立于抗肿瘤活性的调节免疫系统成分的能力，并研究多西他赛和疫苗治疗联合使用的潜在协同活性。我们研究了多西他赛对免疫细胞亚群的体内影响，以及对CD4+、CD8+和T调节细胞（Treg细胞）群体对抗原特异性疫苗应答的功能的影响。我们还在临床前模型中检测了多西紫杉醇和疫苗联合使用的抗肿瘤作用，其中多西紫杉醇对肿瘤生长没有可观察到的影响。这些研究首次表明(a)多西他赛调节非荷瘤小鼠的CD4+、CD8+、CD19+、自然杀伤细胞和Treg群体；(b)与环磷酰胺不同，多西紫杉醇不抑制Tregs的功能；(c)多西他赛增强CD8+而非CD4+对CD3交联的反应；(d)接种后给予多西紫杉醇可最佳增强对重组病毒疫苗的免疫反应；(e)多西紫杉醇联合重组病毒疫苗在减轻肿瘤负担方面优于单独使用任何一种药物；(f)多西紫杉醇加疫苗增加抗原特异性t细胞对疫苗中抗原的反应，以及对来自肿瘤的级联抗原的反应。这些发现提示联合使用多西紫杉醇和重组癌症疫苗的潜在临床益处。

Recombinant poxviruses expressing tumor-associated antigens (TAAs) are currently being evaluated in clinical trials as an approach to treat various cancers. We have previously generated poxviral vectors expressing a TAA and a TRIad of COstimulatory Molecules (B7-1, ICAM-1, and LFA-3; designated TRICOM) as transgenes, including replication competent recombinant vaccinia (rV) or replication-defective modified vaccinia Ankara (MVA), to prime tumor-specific immune responses, and a replication-defective recombinant fowlpox (rF) to boost these responses. MVA is a potentially safer, replication-defective form of vaccinia virus with unique immuno-stimulatory properties that could make it a superior priming vaccine. Here, an MVA vector encoding a tumor antigen (CEA) and TRICOM was utilized (rMVA). A single rMVA-CEA/TRICOM vaccination induced greater expression of several serum cytokines associated with enhanced T-cell immunity than that seen with vaccinia. We hypothesized that this effect might precondition the vaccination site for a more effective boost. An rMVA-CEA/TRICOM prime followed 7 days later (but not 30 days later) by an rF-CEA/TRICOM boost at the same injection site (but not at a distal site) induced more potent CEA-specific T-cell responses, and superior CEA-specific immunity and antitumor activity, than rV-CEA/TRICOM followed by rF-CEA/TRICOM. This preconditioning effect was also observed using a heterologous antigen model, where priming with rMVA-CEA/TRICOM followed 7 days later by rF-LacZ/TRICOM enhanced-beta-gal-specific immunity compared to rF-LacZ/TRICOM only. These studies show for the first time that priming with rMVA followed 7 days later by an rF boost at the same injection site, versus a distal site, generates superior tumor-specific immunity and antitumor activity. Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement. 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 T regulatory cell (Treg cell) 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.