Allogeneic T Cell Responses Against Renal Cell Carcinoma

同种异体 T 细胞对肾细胞癌的反应

• 批准号: 6875804
• 负责人: Edus Houston Warren
• 金额: $ 31.92万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875804
• 关键词: T lymphocyte; clinical research; graft versus host disease; hematopoietic tissue transplantation; histocompatibility; histocompatibility antigens; histocompatibility gene; homologous transplantation; human subject; immune response genes; metastasis; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer remission /regression; patient oriented research; renal cell carcinoma; stem cell transplantation; tumor antigens

DESCRIPTION (provided by applicant): Renal cell carcinoma (RCC) is distinguished amongst solid tumors for its resistance to conventional chemo- and radiotherapy but its susceptibility, in a minority of patients, to immunologic manipulation. Regression of metastatic disease is seen in 10-20% of patients who are treated with the immune-modulating cytokines Interleukin-2 and/or Interferon-alpha, and pilot studies have demonstrated that adoptive cellular therapy with ex vivo-expanded autologous lymphocytes can increase the response rate. More recently, regression of metastatic RCC has also been seen in up to 40% of patients who undergo nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) from donors who are matched at the major histocompatibility complex (MHC). Responses in this setting are typically seen several months or more after HCT, after the establishment of complete donor T cell engraftment, and are closely associated with development of graft-versus-host disease (GVHD). This has suggested that tumor regression may in part be attributable to a graft-versus-tumor (GVT) effect mediated by donor cells reacting with minor histocompatibility (H) antigens expressed on recipient tumor cells. Preliminary data presented in this application demonstrate that T cell clones specific for recipient minor H antigens that are expressed on RCC tumor cells can be isolated from RCC patients experiencing tumor regression after nonmyeloablative allogeneic HCT. Identification of the genes encoding minor H antigens expressed on RCC cells and evaluation of their expression in normal and malignant tissues will facilitate the development of therapeutic strategies for augmenting GVT activity after allogeneic HCT. In this proposal, we will isolate CD8+ and CD4+ RCC-reactive minor H antigen-specific T cell clones from RCC patients after allogeneic HCT and use cellular and molecular methods to identify the genes encoding class I MHC-restricted minor H antigens expressed by RCC cells. The specific aims are: (1) Isolate and characterize CD8+ and CD4+ minor H antigen-specific and tumor-specific T cell clones from RCC patients after nonmyeloablative MHC-identical HCT. (2) Identify clonally expanded T cells that are associated with tumor regression in patients with metastatic RCC following nonmyeloablative MHC-identical HCT. (3) Identify the genes encoding antigens recognized by RCC-reactive CD8+ T cell clones isolated from patients with metastatic RCC who exhibit tumor regression after nonmyeloablative HCT.

描述（由申请人提供）：肾细胞癌（RCC）因其对常规化学和放射疗法的耐药性而在实体瘤中有区别，但在少数患者中，其易感性对免疫学操纵。在10-20％接受免疫调节细胞因子白介素-2和/或干扰素-Alpha治疗的患者中，转移性疾病的消退是可见的，而试验研究表明，通过过多膨胀的自体淋巴细胞的产卵性细胞疗法可以提高响应率。最近，在主要组织相容性复合物（MHC）匹配的供体的供体中，多达40％的患者也可以看到多达40％的转移性RCC的回归。在建立完整的供体T细胞植入后HCT后几个月或更长时间，通常会看到这种情况下的反应，并且与移植物抗宿主病（GVHD）的发展密切相关。这表明肿瘤回归可能部分归因于由供体细胞与在受体肿瘤细胞上表达的较小的组织相容性（H）抗原反应的供体细胞介导的移植物肿瘤（GVT）效应。本应用程序中提供的初步数据表明，可以从反RCC肿瘤细胞表达的受体小型H抗原特异的T细胞克隆从非甲元同种异体同种异体HCT后经历肿瘤退化的RCC患者中分离出来。鉴定编码在RCC细胞上表达的次要H抗原的基因并评估其在正常和恶性组织中的表达将有助于发展治疗策略，以增强同种异体HCT后GVT活性。在该提案中，我们将在同种异体HCT后与RCC患者的CD8+和CD4+ RCC反应小H抗原特异性T细胞克隆分离，并使用细胞和分子方法来识别RCCC细胞表达的I类MHC造成的小型H抗原的基因。具体目的是： （1）在非甲状腺素MHC-认同的HCT后，来自RCC患者的CD8+和CD4+少量H抗原特异性和肿瘤特异性T细胞克隆的分离株和表征。 （2）鉴定在非全能性MHC-相同的HCT后，与转移性RCC患者中与肿瘤消退有关的克隆扩展的T细胞。 （3）确定从转移性RCC患者中分离出的RCC反应CD8+ T细胞克隆识别的抗原的基因，这些基因在非甲状腺不公开HCT后表现出肿瘤退化的患者。