Allogeneic T Cell Responses Against Renal Cell Carcinoma

描述（由申请人提供）：肾细胞癌（RCC）因其对常规化疗和放疗的耐药性而与实体肿瘤区别开来，但在少数患者中，其对免疫操作的易感性。在接受免疫调节细胞因子白介素-2和/或干扰素- α治疗的患者中，10-20%的转移性疾病消退，初步研究表明，采用体外扩增的自体淋巴细胞进行过继细胞治疗可以提高反应率。最近，在接受非清髓性同种异体造血细胞移植（HCT）的患者中，转移性RCC的消退也高达40%，这些患者来自主要组织相容性复合体（MHC）匹配的供体。在这种情况下，反应通常在HCT后数月或更长时间内出现，在建立完整的供体T细胞植入之后，并且与移植物抗宿主病（GVHD）的发展密切相关。这表明肿瘤消退可能部分归因于供体细胞与受体肿瘤细胞表达的少量组织相容性(H)抗原反应介导的移植物抗肿瘤（GVT）效应。本应用程序提供的初步数据表明，可以从非清髓性同种异体HCT后肿瘤消退的RCC患者中分离出表达在RCC肿瘤细胞上的受体次要H抗原的T细胞克隆。鉴定RCC细胞中表达的次要H抗原的编码基因，并评估其在正常和恶性组织中的表达，将有助于制定增强同种异体HCT后GVT活性的治疗策略。在本研究中，我们将从同种异体HCT后的RCC患者中分离CD8+和CD4+ RCC反应性小H抗原特异性T细胞克隆，并使用细胞和分子方法鉴定RCC细胞表达的I类mhc限制性小H抗原编码基因。具体目标是：

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.