Allogeneic T Cell Responses Against Renal Cell Carcinoma

描述（由申请人提供）：肾细胞癌（RCC）在实体瘤中的区别在于其对常规化疗和放疗的抗性，但在少数患者中，其对免疫操作的敏感性。在用免疫调节细胞因子白细胞介素-2和/或干扰素-α治疗的10-20%的患者中观察到转移性疾病的消退，并且初步研究已经证明，用离体扩增的自体淋巴细胞的过继细胞疗法可以增加应答率。最近，在接受非清髓性异基因造血细胞移植（HCT）的患者中，也观察到转移性RCC的消退，这些患者来自主要组织相容性复合体（MHC）匹配的供体。这种情况下的反应通常在HCT后几个月或更长时间，在建立完全供体T细胞植入后观察到，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上表达的次要组织相容性（H）抗原反应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，对RCC肿瘤细胞上表达的受体次要H抗原特异性的T细胞克隆可以从非清髓性同种异体HCT后经历肿瘤消退的RCC患者中分离。鉴定RCC细胞上表达的编码次要H抗原的基因，并评估其在正常和恶性组织中的表达，将有助于开发在同种异体HCT后增强GVT活性的治疗策略。在本研究中，我们将从肾细胞癌患者中分离出同种异体HCT后的CD 8+和CD 4 + RCC反应性次要H抗原特异性T细胞克隆，并使用细胞和分子方法来鉴定RCC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)从非清髓性MHC一致性HCT后的RCC患者中分离并鉴定CD 8+和CD 4+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一致性HCT后，识别与转移性RCC患者肿瘤消退相关的克隆扩增T细胞。 (3)识别从非清髓性HCT后肿瘤消退的转移性RCC患者中分离的RCC反应性CD 8 + T细胞克隆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.