Cellular Immunity Targeting Epithelial Ovarian Cancer

针对上皮性卵巢癌的细胞免疫

• 批准号: 6952122
• 负责人: Richard John O'REILLY
• 金额: $ 15.55万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952122
• 关键词: Epstein Barr virus; SCID mouse; carcinoma; cell line; cellular immunity; clinical research; clinical trial phase I; clinical trial phase II; cytotoxic T lymphocyte; female; human subject; human therapy evaluation; immune response; mucins; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; ovary neoplasms; passive immunization; patient oriented research; tumor antigens; tumor suppressor genes; xenotransplantation

Ovarian carcinoma is the leading cause of death from gynecologic malignancies in the United States, responsible for an estimated 14,000 deaths per year. Despite improvements in therapy, 5-year survival for advanced ovarian cancer remains approximately 20-30%. Ovarian cancers differentially express certain proteins normally present on other tissues only during embryonal development. Among these onco fetal proteins are the WT1 protein, the glycosylated mucin Ca125 (MUC16) and HER2/neu. Recently, we and others have identified potentially immunogenic peptides derived from WT1 and MUC16 which bind the common HLA allele, HLA A0201. Our initial studies with immunogenic WT1 peptides and with candidate MUC16 peptides suggest that these peptides can be used to sensitize T cells from normal individuals and from ovarian cancer patients, which can be expanded in vitro. The T cells sensitized with WT1 and MUC16 generate IFNy and other cytokines in response to peptide and specifically lyse primary HLA A2+ WT1+ or MUC16+ leukemias and selected carcinomas, including ovarian cancer cells in vitro. In a SCID mouse, human tumor xenograft model, we have found that adoptively transferred WT1 specific HLA A2+ T cells home to and specifically induce regressions of certain HLA A2+ WT1+ leukemia and selected carcinomas including ovarian cancer. In this grant, we propose first, to identify and characterize peptides of WT-1 and MUC16 which have moderate to high affinity for HLA A2, and thereafter, other HLA alleles. We will then use EBV BLCL either loaded with WT1, MUC16 or HER2/neu peptides or transduced to express these proteins, for their capacity to sensitize and stimulate the expansion of peptide-specific T cells capable of lysing primary ovarian cancer cells and established cell lines in vitro. We will also explore a novel pentadecapeptide approach to identify novel antigens in WT1 and MUC16. We will then identify features of these tumors which can potentiate or inhibit the tumoricidal activity of these T cells in vitro. We will also comparatively evaluate T cell populations generated from patients and from normal individuals against these peptides to determine whether disparities in phenotypic or functional features of those T cells affect tumor cell interactions in vitro. Third, we will test these peptide-specific cells for their capacity to home to, using a novel in vivo imaging approach, and induce regressions of human ovarian carcinoma xenografts in a SCID mouse model. Lastly, we propose to conduct a phase I/II trial of WT1 or MUC16 peptide-specific T cells in the treatment of women with advanced ovarian carcinoma. These studies may provide important new information regarding the potential of T cells generated ex vivo against these immunogenic peptides for adoptive cell therapy of ovarian cancer.

卵巢癌是美国妇科恶性肿瘤死亡的主要原因，据估计，每年有14,000人死于卵巢癌。尽管治疗方法有所改进，晚期卵巢癌的5年存活率仍保持在20%-30%左右。卵巢癌通常只在胚胎发育期间才有其他组织中存在的某些蛋白质的差异表达。其中包括WT1蛋白、糖化粘蛋白CA125(MUC16)和HER2/neu。最近，我们和其他人发现了来自WT1和MUC16的潜在免疫原肽，它们与常见的HLA等位基因HLAA0201结合。我们对免疫原性WT1多肽和候选MUC16多肽的初步研究表明，这些多肽可以用于增敏正常人和卵巢癌患者的T细胞，这些T细胞可以在体外扩增。用WT1和MUC16致敏的T细胞产生IFNy和其他细胞因子，在体外特异性地杀伤原发的HLAA2+WT1+或MUC16+白血病和选定的肿瘤，包括卵巢癌细胞。在SCID小鼠和人肿瘤异种移植模型中，我们发现过继转移WT1特异性的HLAA2+T细胞可以特异性地诱导某些HLAA2+WT1+白血病和包括卵巢癌在内的特定肿瘤的消退。在这项资助中，我们建议首先鉴定和鉴定WT-1和MUC16与HLAA2具有中到高亲和力的多肽，然后鉴定其他HLAA2等位基因。然后，我们将使用EBV BLCL负载WT1、MUC16或HER2/neu多肽或转导表达这些蛋白，以检测它们对能够在体外裂解原代卵巢癌细胞和已建立的细胞系的多肽特异性T细胞的敏感性和刺激其增殖的能力。我们还将探索一种新的十五肽方法来识别WT1和MUC16中的新抗原。然后，我们将确定这些肿瘤的特征，在体外可以增强或抑制这些T细胞的杀瘤活性。我们还将比较评估患者和正常人产生的T细胞群与这些 以确定这些T细胞在表型或功能特征上的差异是否会影响体外肿瘤细胞的相互作用。第三，我们将使用一种新的体内成像方法测试这些多肽特异性细胞的归宿能力，并在SCID小鼠模型中诱导人卵巢癌异种移植瘤的消退。最后，我们建议进行WT1或MUC16多肽特异性T细胞治疗晚期卵巢癌妇女的I/II期试验。这些研究可能为卵巢癌的过继细胞治疗提供重要的新信息，即体外产生的针对这些免疫原肽的T细胞的潜力。