Targeting Novel T Cell Antigens on Renal Cell Carcinoma

描述（由申请人提供）：转移性肾细胞癌（RCC）对大多数常规癌症治疗反应较差，但在接受非特异性免疫疗法（如白细胞介素-2或干扰素- 1）治疗的患者中，10-20%的转移性肾细胞癌出现消退。值得注意的是，一小部分对细胞因子治疗有反应的患者实现了疾病的持久完全缓解。系统给予细胞因子治疗的抗肿瘤作用尚不完全清楚，但被认为可以增强能够识别RCC肿瘤的宿主细胞免疫反应。然而，由于缺乏合适的RCC靶抗原，RCC特异性免疫治疗的发展一直受到阻碍。最近，低强度异体造血细胞移植（HCT）作为转移性RCC过继免疫治疗的一种新形式的初步研究已经报道了在这种方式治疗的一部分患者中部分或完全的肿瘤反应。反应通常发生在HCT后几个月，在供体T细胞完全植入后，并且与移植物抗宿主病的发展密切相关，这表明在这种情况下，识别受体组织和RCC肿瘤细胞上表达的次要组织相容性(H)抗原的同种反应性T细胞介导了移植物抗肿瘤效应。本应用中的数据表明，CD8+细胞毒性T淋巴细胞（CTL）克隆定义了在RCC肿瘤细胞上表达的多种不同的次要H抗原，可以从经过低强度异体HCT后肿瘤消退或稳定的RCC患者中分离出来。鉴定编码这些次要H抗原的基因及其组织表达的特征可以确定免疫治疗的潜在靶点，并可以为有效抗肿瘤免疫应答的要求提供有价值的见解。该应用程序包括实验室和临床研究，旨在开发针对RCC肿瘤的次要H抗原的特异性免疫疗法。具体目标是：

DESCRIPTION (provided by applicant): Metastatic renal cell carcinoma (RCC) is poorly responsive to most conventional cancer therapy, but regression of metastatic RCC is seen in 10-20% of patients treated with non-specific immunotherapies such as interleukin-2 or interferon-(. Remarkably, a small percent of patients responding to cytokine therapy achieve durable complete remission of their disease. The anti-tumor effect of systemically administered cytokine therapy is not completely understood, but is thought to augment a host cellular immune response capable of recognizing RCC tumor. Development of specific immunotherapy for RCC, however, has been hindered by the lack of suitable target antigens on RCC cells. Recently, pilot studies of reduced intensity allogeneic hematopoietic cell transplantation (HCT) as a novel form of adoptive immunotherapy for metastatic RCC have reported partial or complete tumor responses in a subset of patients treated in this fashion. Responses are typically seen several months after HCT, after development of complete donor T cell engraftment, and are closely associated with the development of graft-versus-host disease, suggesting that allo-reactive T cells recognizing minor histocompatibility (H) antigens expressed on recipient tissues and RCC tumor cells mediate a graft-versus-tumor effect in this setting. Data presented in this application demonstrate that CD8+ cytotoxic T lymphocyte (CTL) clones defining multiple distinct minor H antigens that are expressed on RCC tumor cells can be isolated from RCC patients experiencing tumor regression or stabilization after reduced intensity allogeneic HCT. Identification of the genes encoding these minor H antigens and characterization of their tissue expression may identify potential targets for immunotherapy, and could provide valuable insight into the requirements for an effective anti-tumor immune response. This application comprises laboratory and clinical studies designed to develop specific immunotherapy targeting minor H antigens on RCC tumor. The Specific Aims are: 1. To identify the genes that encode minor H antigens recognized by RCC-reactive CD8+ CTL clones isolated from RCC patients treated by allogeneic HCT, and to quantify their expression in normal and malignant tissues. 2. To evaluate the safety, in vivo persistence, and anti-tumor efficacy of adoptively transferred RCC-reactive T cell clones in patients with metastatic RCC. Limited treatment options are presently available for advanced kidney cancer (renal cell carcinoma). Allogeneic stem cell transplantation is a unique form of immune therapy that can be effective for some patients with kidney cancer. Identifying the key components of the tumor-specific immune response that occurs after such transplants may foster the development of novel and more effective immune therapies for this cancer.