B7.1 COSTIMULATION IN OVARIAN CANCER

B7.1 卵巢癌的协同刺激

• 批准号: 6046172
• 负责人: RALPH Stuart FREEDMAN
• 金额: $ 14.41万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6046172
• 关键词: clinical research; cytotoxic T lymphocyte; human subject; human therapy evaluation; intraperitoneal injections; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; ovary neoplasms; vaccine development; vector vaccine

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.

描述：（申请人的摘要）这项研究的长期目标是 为卵巢癌患者开发免疫疗法，涉及 腹膜内（IP）注射（a）X辐照自体肿瘤细胞的注射 具有人类共同刺激分子HB7.1的转基因和（b） RLFN-GAMMA（G）。卵巢癌症是发病率和 死亡率和治愈率几乎没有提高。实验性肿瘤的结果 模型表明，通过B7/CD28途径进行共刺激 诱导肿瘤需要免疫原性（MHC表达） 在体内有效的肿瘤特异性免疫。确定是否共刺激 HB7.1促进卵巢患者的肿瘤特异性免疫反应 癌症是一种新型的肿瘤疫苗策略。这 策略由用HB7.1转导的自体肿瘤细胞组成 B7.1编码的CanaryPox载体Alvac-HB7.1感染（Pasteur merieux 康纳特）。 HLA I类和HLA II类在卵巢癌细胞上的表达 通常会减少，并且可以通过注入RLFN-G来逆转此效果 腹膜内。因此，RLFN-G将两者都用于准备 疫苗和体内促进肿瘤特异性免疫反应。这 申请人的具体目的是：（1）确定IP注射是否是否 由B7.1修饰的自体肿瘤细胞和RLFN-G组成的肿瘤疫苗， 导致表现出（a）细胞毒性的T淋巴细胞体内发育 主要局限于自体肿瘤细胞，（b）Th1或Th2细胞因子 响应自体肿瘤而不是正常细胞的产生，（c） T细胞上的早期中期和晚期激活抗原。 （2）确定 肿瘤细胞疫苗是否促进了T细胞系的产生（或 源自腹膜肿瘤浸润淋巴细胞（TIL）的克隆）， 这些T细胞线（或克隆）是否表现出增加的细胞毒性活性 或针对自体肿瘤细胞的细胞因子产生。 （3）确定（a） T细胞对肿瘤疫苗的反应是否与成熟有关 腹膜抗原在体内呈递细胞，（b）T细胞是否是否 腹膜腔DR+单核细胞在体外抑制反应 分泌IL-10和TGF-beta，以及这些影响是否可以逆转 针对TGF-β和IL-10受体的单克隆抗体。意义： 提出的研究将提高有关以下方面的知识：（a）卵巢的治疗 癌症，（b）可能用于用于用于用于的TIL衍生的T细胞系 收养免疫疗法，以及（c）某些因素的体内作用 干扰T细胞激活和（d）未来临床试验的方向 与这些代理。