DESIGN OF LIVE RECOMBINANT VACCINES FOR ACTIVE SPECIFIC IMMUNOTHERAPY

正在进行的研究包括构建和临床前评估 表达重组痘病毒的安全性和免疫原性 人类肿瘤相关抗原。其中包括癌胚抗原。 (CEA)、前列腺特异性抗原(PSA)与人类乳腺癌 抗原，MUC1。我们证明了CEA可以被用作 主动特异性免疫治疗。重组疫苗免疫小鼠的研究 表达CEA的痘苗病毒(RV-CEA)可诱导抗肿瘤作用 活动。表达PSA和MUC1的重组痘苗病毒也 被发现是安全的疫苗并诱导出适当的抗肿瘤 回应。RV-PSA免疫恒河猴可诱导产生PSA- 特异性体液免疫反应和细胞免疫反应。五花八门 通过T细胞表面分子传递的共刺激信号是 抗原靶标激活初始T细胞所必需的 细胞。B7基因家族以及其他基因的表达 共刺激分子，如CD70，LFA3和ICAM-1已被发现 是诱导和维护的重要组成部分 实验模型中的抗肿瘤反应。我们已经建造了和 评估重组痘苗病毒表达B7-1的能力， B7-2、CD70、LFA3和ICAM-1在细胞内传递共刺激分子 抗原提呈部位与增强细胞介导的抗肿瘤作用 回应。RV-B7-1、B7-2和ICAM-1感染肿瘤细胞 结果在动物体内没有肿瘤生长，而肿瘤细胞感染 与野生型牛痘病毒一起导致肿瘤生长和死亡 主持人。这些研究证明了它的实用性和易用性 重组痘苗病毒将共刺激分子运送到肿瘤 用于潜在基因治疗和重组癌症方法的细胞 免疫疗法。我们还演示了将它们混合在一起的用途 重组共刺激痘苗病毒与RV-CEA和RV-MUC1TO 增强肿瘤相关抗原特异性T细胞反应与抗肿瘤 小鼠肿瘤模型中的免疫作用。提高T细胞免疫原性的研究 而肿瘤相关抗原疫苗的特异性已经被 通过构建含有以下成分的重组痘苗病毒来完成 肿瘤相关免疫优势表位的最小决定因素 抗原。表达肿瘤相关基因的第二代疫苗 正在使用非复制的痘病毒来开发抗原，例如 禽痘、鸡痘和改良安卡拉牛痘。

Ongoing studies involve the construction and preclinical evaluation of the safety and immunogenicity of recombinant pox viruses expressing human tumor associated antigens. These include carcinoembryonic antigen (CEA), prostate specific antigen (PSA), and the human breast cancer antigen, MUC1. We demonstrated that CEA could be used as a target for active specific immunotherapy. Immunization of mice with a recombinant vaccinia virus expressing CEA (rV-CEA) was able to elicit antitumor activity. Recombinant vaccinia viruses expressing PSA and MUC1 were also found to be safe vaccines and to elicit the appropriate anti-tumor responses. Rhesus monkeys immunized with rV-PSA were able to elicit PSA- specific humoral as well as cell-mediated immune responses. Various costimulatory signals delivered through T-cell surface molecules are required for the activation of naive T-cells by antigen-bearing target cells. The expression of the B7 gene family as well as other costimulatory molecules, such as CD70, LFA3 and ICAM-1, have been shown to be an important component for the induction and maintenance of antitumor responses in experimental models. We have constructed and evaluated the ability of recombinant vaccinia viruses expressing B7-1, B7-2, CD70, LFA3 and ICAM-1 to deliver costimulatory molecules at the site of antigen presentation and enhance cell mediated anti-tumor responses. Tumor cells infected with rV-B7-1 and B7-2 and ICAM-1 resulted in no tumor growth in the animals, while tumor cells infected with wild type vaccinia virus led to tumor growth and the death of the host. These studies demonstrated the utility and ease of using recombinant vaccinia viruses to deliver costimulatory molecules to tumor cells for potential gene therapy and recombinant approaches to cancer immunotherapy. We have also demonstrated the utility of admixing these recombinant costimulatory vaccinia viruses with rV-CEA and rV-MUC1 to enhance tumor associated antigen-specific T-cell responses and antitumor immunity in murine tumor models. Improvement of T-cell immunogenicity and specificity of tumor associated antigen vaccines has been accomplished by constructing recombinant vaccinia viruses containing minimal determinants of an immunodominant epitope of tumor associated antigens. Second generation vaccines expressing tumor associated antigens are being developed using nonreplicating pox viruses such as avipox, fowl pox and MVA (Modified Vaccinia Ankara).