B7.1 COSTIMULATION IN OVARIAN CANCER

描述：(申请人摘要)这项研究的长期目标是 为卵巢癌患者开发免疫疗法，包括 (A)X-射线照射的自体肿瘤细胞的腹膜内注射 有人类共刺激分子hB7.1的转基因，和(B) R1Fn-Gamma(G)。卵巢癌病是发病率和死亡率的重要原因 死亡率和治愈率几乎没有改善。实验肿瘤的结果 模型表明，通过B7/CD28途径和 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。以确定共刺激信号是否 HB7.1促进卵巢癌患者的肿瘤特异性免疫反应 癌症，一种新的肿瘤疫苗策略已经被开发出来。这 策略包括转导hB7.1的自体肿瘤细胞 B7.1编码的金丝雀痘载体ALVAC-hB7.1(巴斯德)的感染 诺特)。卵巢癌细胞表面人类白细胞抗原I、II类分子的表达 通常会降低，这种作用可以通过注射rlFn-g来逆转 在腹膜内。因此，rlFN-g将用于制备 该疫苗和体内促进肿瘤特异性免疫反应。这个 申请者的具体目标是：(1)确定IP注射是否 由B7.1修饰的自体肿瘤细胞和r1FN-g组成的肿瘤疫苗， 显示(A)细胞毒性的T淋巴细胞在体内发育的结果 主要限于自体肿瘤细胞，(B)TH1或TH2细胞因子 产生对自体肿瘤的反应，但不对正常细胞产生，以及(C) T细胞上的早、中、晚活化抗原。(二)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性淋巴细胞(TIL)， 这些T细胞系(或克隆)是否表现出更强的细胞毒活性 或产生细胞因子来对抗自体肿瘤细胞。(3)决定(A) T细胞对肿瘤疫苗的反应是否与其成熟有关 体内的腹膜抗原提呈细胞，以及(B)T细胞是否 在体外，腹膜腔DR+单核细胞可抑制反应 分泌IL-10和转化生长因子-β，以及这些作用是否可以被逆转 抗转化生长因子-β和IL-10受体的单抗。重要意义： 建议的研究将增进对以下方面的了解：(A)卵巢疾病的治疗 癌症，(B)TIL来源的T细胞系的发展，可能用于 过继免疫疗法，以及(C)某些因素在体内的作用 干扰T细胞激活，以及(D)未来临床试验的方向 和这些特工在一起。

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.