B7.1 COSTIMULATION IN OVARIAN CANCER

描述：（申请人摘要）本研究的长期目标是 为卵巢癌患者开发免疫疗法， 腹膜内（IP）注射（a）X-照射的自体肿瘤细胞， 具有人共刺激分子hB7.1的转基因，和（B） rIFN-γ（g）。卵巢癌病是发病的重要原因， 死亡率和治愈率几乎没有改善。实验性肿瘤的结果 模型表明，通过B7/CD28通路的共刺激和 肿瘤的免疫原性（MHC表达）是诱导 体内有效的肿瘤特异性免疫。为了确定共刺激是否 hB7.1促进卵巢癌患者的肿瘤特异性免疫应答 癌病，一种新的肿瘤疫苗策略已经开发出来。这 策略包括用hB7.1转导的自体肿瘤细胞， 用B7.1编码的金丝雀痘载体ALVAC-hB7. 1（Pasteur Merieux）感染 康诺特）。卵巢癌细胞中HLA I类和HLA II类分子的表达 通常会降低，并且这种作用可以通过注射rIFN-g来逆转 腹腔注射因此，rIFN-g将用于制备 疫苗和体内以促进肿瘤特异性免疫应答。的 申请人的具体目标是：（1）确定IP注射是否 由B7.1修饰的自体肿瘤细胞和rIFN-g组成的肿瘤疫苗， 导致体内T淋巴细胞的发育，其表现出（a）细胞毒性 主要限于自体肿瘤细胞，（B）TH1或TH2细胞因子 响应于自体肿瘤而非正常细胞的产生，和（c） T细胞上的早期、中期和晚期活化抗原。(2)以确定 肿瘤细胞疫苗是否促进T细胞系的产生（或 克隆）来源于腹膜肿瘤浸润淋巴细胞（TIL）， 以及这些T细胞系（或克隆）是否表现出增加的细胞毒活性 或针对自体肿瘤细胞的细胞因子产生。(3)确定（a） T细胞对肿瘤疫苗的应答是否与肿瘤细胞的成熟有关， 体内腹膜抗原呈递细胞，和（B）T细胞是否 反应在体外被腹膜腔DR+单核细胞抑制， 分泌IL-10和TGF-β，以及这些作用是否可以通过 针对TGF-β和IL-10受体的单克隆抗体。重要性： 提出的研究将推进以下方面的知识：（a）卵巢癌的治疗 （B）TIL衍生的T细胞系的开发，其可用于 过继性免疫疗法，和（c）某些因子的体内作用， 干扰T细胞活化，以及（d）未来临床试验的方向 与这些代理人。

DESCRIPTION: (Applicant's Abstract) The long-term goal of this study is to develop immunotherapy for patients with ovarian carcinomatosis that involves intraperitoneal (IP) injections of (a) x-irradiated autologous tumor cells that have the transgene for the human costimulatory molecule hB7.1, and (b) rlFN-gamma (g). Ovarian carcinomatosis is a significant cause of morbidity and mortality and cure rates have improved little. Results from experimental tumor models suggest that costimulation through the B7/CD28 pathway and immunogenicity (MHC expression) of the tumor are required for the induction of effective tumor specific immunity in vivo. To determine whether costimulation with hB7.1 facilitates tumor-specific immune responses in patients with ovarian carcinomatosis, a novel tumor-vaccine strategy has been developed. This strategy consists of autologous tumor cells transduced with hB7.1 following infection with the B7.1 encoded canarypox vector, ALVAC-hB7.1 (Pasteur Merieux Connaught). HLA Class I and HLA Class II expression on ovarian carcinoma cells is often reduced, and this effect can be reversed by injecting rlFN-g intraperitoneally. Therefore, rlFN-g will be used both in the preparation of the vaccine and in vivo to facilitate tumor specific immune responses. The applicant's specific aims are: (1) To determine whether IP injections of a tumor vaccine consisting of B7.1-modified autologous tumor cells and rlFN-g, results in development in vivo of T lymphocytes that exhibit (a) cytotoxicity primarily restricted to autologous tumor cells, (b) TH1 or TH2 cytokine production in response to autologous tumor but not to normal cells, and (c) early intermediate and late activation antigens on T-cells. (2) To determine whether the tumor-cell vaccine facilitates production of T-cell lines (or clones) that are derived from peritoneal tumor infiltrating lymphocytes (TIL), and whether these T-cell lines (or clones) exhibit increased cytotoxic activity or cytokine production against autologous tumor cells. (3) To determine (a) whether T-cell responses to the tumor vaccine are associated with maturation of peritoneal antigen-presenting cells in vivo, and (b) whether the T-cell responses are inhibited in vitro by peritoneal cavity DR+ monocytes that secrete IL-10 and TGF-beta, and whether these effects can be reversed by monoclonal antibodies against TGF-beta and the IL-10 receptor. Significance: The studies proposed will advance knowledge about: (a) treatment for ovarian cancer, (b) development of TIL-derived T-cell lines that might be used for adoptive immunotherapy, and (c) the in vivo role of certain factors that interfere with T-cell activation, and (d) directions for future clinical trials with these agents.