Targeting Novel T Cell Antigens on Renal Cell Carcinoma

描述(申请人提供)：转移性肾细胞癌(RCC)对大多数传统癌症治疗反应不佳，但在接受非特异性免疫治疗的患者中，转移性RCC消退的比例为10%-20%，如白细胞介素2或干扰素。值得注意的是，对细胞因子治疗有反应的一小部分患者实现了疾病的持久完全缓解。全身应用细胞因子治疗的抗肿瘤作用尚不完全清楚，但被认为增强了能够识别肾癌肿瘤的宿主细胞免疫反应。然而，由于缺乏合适的靶抗原，肾细胞癌的特异性免疫治疗的发展一直受到阻碍。最近，低强度同种异体造血细胞移植(HCT)作为转移性肾细胞癌过继免疫治疗的一种新形式的试点研究报告了以这种方式治疗的部分患者的部分或全部肿瘤反应。反应通常出现在HCT后几个月，即供者T细胞完全植入后，并与移植物抗宿主病的发生密切相关，这表明识别受体组织和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细胞在这种情况下介导了移植物抗肿瘤效应。本申请中提供的数据表明，CD8+细胞毒性T淋巴细胞(CTL)克隆可以从肾细胞癌患者中分离出来，这些细胞毒性T淋巴细胞(CTL)克隆定义了肾癌肿瘤细胞上表达的多种不同的微小H抗原，这些患者在降低强度的同种异体HCT后经历了肿瘤的消退或稳定。识别编码这些微小H抗原的基因及其组织表达的特征可能会识别免疫治疗的潜在靶点，并可能为有效的抗肿瘤免疫反应提供有价值的见解。这一应用包括实验室和临床研究，旨在开发针对肾癌肿瘤的微小H抗原的特异性免疫疗法。具体目标是： 1.鉴定RCC反应性CD8+CTL克隆识别微小H抗原的基因，并对其在正常和恶性肾细胞癌组织中的表达进行定量研究。 2.评价过继转移的肾癌反应性T细胞克隆在转移性肾癌患者中的安全性、体内持久性和抗肿瘤效果。 目前，晚期肾癌(肾细胞癌)的治疗选择有限。异基因干细胞移植是一种独特的免疫疗法，可以有效地治疗一些肾癌患者。识别这种移植后发生的肿瘤特异性免疫反应的关键成分可能会促进针对这种癌症的新的、更有效的免疫疗法的开发。

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.