Vaccine and Drug Combination Therapy for Human Cancers

表达肿瘤相关抗原（TAA）的重组痘病毒目前正在研究中。 在临床试验中评估作为治疗各种癌症的方法。我们先前已经 产生表达共刺激分子的TAA和TRIad的痘病毒载体（B7-1， ICAM-1和LFA-3;命名为TRICOM）作为转基因，包括复制能力 重组牛痘（rV）或复制缺陷型修饰的安卡拉牛痘（MVA），以引发 肿瘤特异性免疫反应，以及复制缺陷型重组鸡痘（rF），以加强 这些回应。MVA是一种潜在更安全的复制缺陷型牛痘病毒， 独特的免疫刺激特性使其成为一种上级引发疫苗。这里是 使用编码肿瘤抗原（CEA）和TRICOM的MVA载体（rMVA）。单个 rMVA-CEA/TRICOM疫苗接种诱导了几种血清相关细胞因子的更高表达， T细胞免疫力比接种牛痘疫苗时增强。我们假设这种效应 可能会使疫苗接种部位更有效地加强。rMVA-CEA/TRICOM预充 7天后（但不是30天后），在同一次注射中进行rF-CEA/TRICOM加强 位点（但不在远端位点）诱导更有效的CEA特异性T细胞应答， 上级CEA特异性免疫和抗肿瘤活性优于rV-CEA/TRICOM，其次是 rF-CEA/TRICOM。使用异源抗原也观察到这种预处理效应 模型，其中先用rMVA-CEA/TRICOM引发，7天后用rF-LacZ/TRICOM引发 与仅rF-LacZ/TRICOM相比，增强的β-gal特异性免疫。这些研究表明， 第一次用rMVA引发，7天后用相同浓度的rF加强。 与远端部位相比，注射部位产生上级肿瘤特异性免疫和抗肿瘤 活动多西他赛和重组疫苗的组合增强T细胞应答， 抗肿瘤活性：多西他赛对免疫增强的作用。紫杉烷类包括一些 最广泛使用的癌症化疗剂。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。这 这项研究旨在确定这种紫杉烷是否具有调节 免疫系统独立的抗肿瘤活性，并研究潜在的协同作用 多西他赛和疫苗疗法的组合的活性。我们检查了体内 多西他赛对免疫细胞亚群及CD 4+、CD 8+和T细胞功能的影响 调节性细胞（Treg细胞）群体对抗原特异性疫苗接种的应答。我们也 在临床前研究中检查了多西他赛和疫苗组合的抗肿瘤作用， 多西他赛对肿瘤生长无明显影响的模型。这些研究表明， 多西他赛首次调节CD 4+、CD 8+、CD 19+、自然杀伤细胞和Treg （B）与环磷酰胺不同，多西他赛不抑制 （c）多西他赛增强对CD 3交联的CD 8+而不是CD 4+应答; (d)疫苗接种后给予多西他赛可最佳增强免疫应答， 重组病毒疫苗;（e）多西他赛联合重组病毒疫苗更优上级 与单独的任一种药物相比降低肿瘤负荷;和（f）多西他赛加疫苗增加 对疫苗中的抗原以及级联抗原的抗原特异性T细胞应答 来源于肿瘤。这些发现表明联合使用的潜在临床获益 多西他赛和重组癌症疫苗。

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.