Cellular Immunity Targeting Epithelial Ovarian Cancer

针对上皮性卵巢癌的细胞免疫

基本信息

批准号：
7902226
负责人：
Richard John O'REILLY
金额：
$ 36.22万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7902226
关键词：
Affect Affinity Alleles Antigens B-Lymphocytes Binding CA-125 Antigen Cancer Patient Carcinoma Cause of Death Cell Communication Cell Therapy Cells Cellular Immunity Cessation of life Clinical Trials Cytolysis Development ERBB2 gene Epithelial ovarian cancer Epitopes Fetal Proteins Generations Grant Gynecologic Home environment Human Human Herpesvirus 4 Human WT1 Genes Image In Vitro Individual Malignant Neoplasms Malignant neoplasm of ovary Mucins Ovarian Carcinoma Parents Patients Peptides Phase Phase I/II Trial Population Pre-Clinical Model Proteins SCID Mice T-Lymphocyte Testing Tissues Tumor Cell Line United States WT1 Protein WT1 gene Woman Xenograft Model Xenograft procedure base cancer cell cytokine established cell line immunogenic in vitro activity in vivo leukemia mouse model neoplastic cell novel ovarian neoplasm programs response tumor tumor xenograft vector

项目摘要

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，估计每年造成14,000人死亡。尽管治疗有所改善，但晚期卵巢癌的5年生存率仍约为20-30％。卵巢癌仅在胚胎发育过程中差异地表达通常存在于其他组织上的某些蛋白质。在这些onco胎儿蛋白中，有WT1蛋白，糖基化的粘蛋白CA125（MUC16）和HER2/NEU。最近，我们和其他人确定了源自WT1和MUC16的潜在免疫原性肽，它们结合了共同的HLA等位基因HLA A0201。我们对免疫原性WT1肽以及候选MUC16肽的初步研究表明，这些肽可用于使来自正常个体的T细胞和卵巢癌患者敏感，这些肽可以在体外扩展。与WT1和MUC16敏化的T细胞可对肽，特别是裂解原发性HLA A2+ WT1+或MUC16+白血病以及选定的癌（包括卵巢癌细胞），从而产生IFNY和其他细胞因子。在SCID小鼠的人类肿瘤异种移植模型中，我们发现，经过的WT1特异性HLA A2+ T细胞转移到家中，并特别诱导某些HLA A2+ WT1+白血病的回归和包括卵巢癌（包括卵巢癌）的选定癌。在这笔赠款中，我们首先建议识别和表征WT-1和MUC16的肽，这些肽对HLA A2具有中等至高的亲和力，此后，其他HLA等位基因。然后，我们将使用带有WT1，MUC16或HER2/NEU肽的EBV BLCL或转导的EBV BLCL来表达这些蛋白质，以使其能够敏感和刺激能够溶解原发性卵巢癌细胞并在体外建立细胞系的肽特异性T细胞的扩张。我们还将探索一种新型的五二肽方法，以鉴定WT1和MUC16中的新型抗原。然后，我们将确定这些肿瘤的特征，这些肿瘤可以在体外增强或抑制这些T细胞的肿瘤活性。我们还将相对评估患者和正常个体产生的T细胞群体肽确定这些T细胞的表型或功能特征的差异是否会在体外影响肿瘤细胞相互作用。第三，我们将使用一种新型的体内成像方法测试这些肽特异性细胞的回家能力，并在SCID小鼠模型中诱导人卵巢癌异种移植物的回归。最后，我们建议在治疗晚期卵巢癌女性中对WT1或MUC16肽特异性T细胞进行I/II期试验。这些研究可能会提供有关T细胞对这些免疫原性肽产生的T细胞的潜力来提供的重要新信息。