OVARIAN CARCINOMA TIL TREATMENT AFTER IFN GAMMA/IL2

该交互式R01提案的长期目标是开发 上皮性卵巢癌新的有效治疗方法 (EOC)基于体内肿瘤浸润性淋巴细胞的激活 (TIL)是针对自体肿瘤的。尽管最近在 卵巢癌的化疗对这些患者的生存有很大的影响 想要。在这项拨款申请中要检验的假设是 卵巢TIL来源的T细胞系可从腹膜渗出液中培养出来 卵巢癌患者经腹膜腔内注射卡介苗后细胞的变化 干扰素-lambda(rLFN-lambda)，然后小剂量IL-2。在……里面 具体地说，我们将解决IP启动是否使用这些 细胞因子与(A)肿瘤细胞比例增加有关 体内表达MHC I类和/或II类表面抗原的；(B) 人外周血中大量CD3+TCRAlphabeta+淋巴细胞的回收 腹膜腔(P.C.)表达CD8+或CD4+表型；(C) 利用PEC扩增CD8+或CD4+T细胞系的能力 T细胞纯化程序和(D)获得的T细胞株 重组人干扰素-lambda诱导后，在(I_1)方面表现出特异性 自体肿瘤细胞的杀伤活性和/或(Ii)细胞因子的产生。 所有这些假说都集中在阐明作用机制上， 在活体内，这些TIL中的一种，只能与 EoC患者采用以下策略治疗的临床试验 体内获得的过继转移的TIL(PEC) 用重组人干扰素-lambda和IL-2预注。临床试验遵循的是一项基本的 我们在EoC IP过继免疫治疗试验中使用的设计 病人。用rIFN-lambda进行ip免疫是我们试验的一个新特点。 设计。(E)我们还将在单独的方案中检验这一假设 卵巢TIL来源的T细胞株在术后肿瘤部位集中 IP注入。我们的具体目标是：确定IP启动是否 RIFN-lambda和小剂量rIL-2与卵巢癌患者的相关性 随着(1)MHC I类或II类表面抗原表达增加 (2)卵巢TIL来源T细胞的产生 来自PEC的(A)表达CD8+TCRalphabeta+或 CD4+TCRAlphabeta+表型，以及(B)在 自体肿瘤细胞毒性和/或(Ii)细胞因子术语 制作。其他具体目标是(3)确定频率和 中毒事件和/或临床反应的强度 包括用细胞因子和IP启动IP的治疗策略 重组人干扰素-lambda治疗后细胞因子诱导的T细胞株和 小剂量rIL-2，(4)测定纯化的卵巢T细胞的能力 集中在肿瘤部位的队伍。

The long-term objectives of this interactive R01 proposal are to develop new and effective treatment approaches for epithelial ovarian cancer (EOC) based upon the activation in vivo of tumor infiltrating lymphocytes (TIL) specific for autologous tumor. Notwithstanding recent advances in the chemotherapy of EOC the survival of these patients leaves much to be desired. The hypotheses to be tested in this grant application are that ovarian TIL-derived T-cell lines can be developed from peritoneal exudate cells (PEC) of EOC patients after intraperitoneal (IP) priming with interferon-lambda (rLFN-lambda) followed by low doses of IL-2. In particular, we will address the issues whether IP priming with these cytokines is correlated with (a) increased proportions of tumor cells that express MHC Class I and/or Class II surface antigens in vivo; (b) recovery of large numbers of CD3+TCRalphabeta+ lymphocytes from the peritoneal cavity (P.c.) that express either CD8+ or CD4+ phenotypes; (c) an ability to expand either CD8+ or CD4+ T-cell lines from PEC utilizing a T cell purification procedure and (d) that the T-cell lines obtained after IP priming with rIFN-lambda exhibit specificity in terms of (i_ autologous tumor cell cytolytic activity and/or (ii) cytokine production. All these hypotheses are focused on elucidating the mechanisms of action, in vivo, of these TILs and can be addressed only in conjunction with a clinical trial in which patients with EOC are treated with a strategy of adoptively transferred TIL developed from (PEC) obtained after in vivo priming with rIFN-lambda and IL-2. The clinical trial follows a basic design that we have used in IP adoptive immunotherapy trials of EOC patients. IP priming with rIFN-lambda is a novel feature of our trial design. (e) We will also test the hypothesis in a separate protocol that: ovarian TIL-derived T-cell lines concentrate at tumor sites after IP injection. Our specific aims are to: Determine whether IP priming of EOC patients with rIFN-lambda followed by low dose rIL-2 correlates with (1) Increased expression of MHC Class I or Class II surface antigens on EOC cells in vivo, and (2) Production of ovarian TIL-derived T-cell lines from PEC that (a) express either the CD8+TCRalphabeta+ or CD4+TCRalphabeta+ phenotype, and (b) exhibit tumor specific activity in terms of (i) Autologous tumor cell cytotoxicity and/or (ii) cytokine production. Other specific aims are to (3) Determine the frequency and intensity of toxic events and/or clinical responses that result from a treatment strategy that includes IP priming with cytokines and IP treatment with rIFN-lambda followed by cytokine primed T-cell lines and low dose rIL-2, and (4) Determine the ability of purified ovarian T-cell lines to concentrate at tumor sites.