Allogeneic T Cell Responses Against Renal Cell Carcinoma

描述(申请人提供)：肾细胞癌(RCC)与实体瘤的区别在于它对传统的化疗和放射治疗耐药，但在少数患者中，它对免疫操作敏感。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，转移性疾病的消退率为10%-20%，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应答率。最近，在接受来自主要组织相容性复合体(MHC)匹配的供者的非清髓性异基因造血细胞移植(HCT)的患者中，也有高达40%的转移性肾癌消退。在这种情况下，反应通常出现在HCT后几个月或更长时间，在供者T细胞完全植入后，并与移植物抗宿主病(GVHD)的发展密切相关。这表明肿瘤的消退可能部分归因于供体细胞与受体肿瘤细胞上表达的次要组织相容性(H)抗原反应所介导的移植物抗肿瘤(GVT)效应。本申请中提供的初步数据表明，在RCC肿瘤细胞上表达的针对受体次要H抗原的T细胞克隆可以从非清髓性异基因HCT后肿瘤消退的RCC患者中分离出来。识别肾细胞癌细胞上表达的微小H抗原基因，并对其在正常和恶性组织中的表达进行评估，将有助于开发提高异基因HCT后GVT活性的治疗策略。在这项研究中，我们将从异基因HCT后的肾癌患者中分离CD8+和CD4+RCC反应的次要H抗原特异性T细胞克隆，并使用细胞和分子方法鉴定肾癌细胞表达的编码I类MHC限制性次要H抗原的基因。具体目标是： (1)分离和鉴定非清髓性MHC相合红细胞移植后肾细胞癌患者CD8+和CD4+次要H抗原特异性和肿瘤特异性T细胞克隆。 (2)在非清髓性MHC相合的HCT后的转移性肾癌患者中，确定克隆性扩增的T细胞与肿瘤消退相关。 (3)从非清髓性HCT后肿瘤消退的转移性肾癌患者中分离RCC反应性CD8+T细胞克隆，鉴定其识别的抗原编码基因。

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.