Targeting Novel T Cell Antigens on Renal Cell Carcinoma

靶向肾细胞癌的新型 T 细胞抗原

• 批准号: 7664470
• 负责人: SCOTT S TYKODI
• 金额: $ 13.45万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664470
• 关键词: Adoptive Immunotherapy; Allogenic; Antigen Targeting; Antigens; CD8B1 gene; Cell Therapy; Cell Transplantation; Cells; Clinical Research; Cytotoxic T-Lymphocytes; Data; Development; Disease; Disease remission; Engraftment; Fostering; Foundations; Genes; Graft-Versus-Tumor Induction; Hematopoietic; Histocompatibility; Immune response; Immunotherapy; Interferons; Interleukin-2; Laboratories; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metastatic Renal Cell Cancer; Minor; Normal tissue morphology; Patients; Pilot Projects; Renal Cell Carcinoma; Renal carcinoma; Reporting; Research Design; Safety; Stem cell transplant; T-Lymphocyte; Tissues; Transplantation; bacterial H antigen; cancer therapy; cytokine therapy; experience; graft vs host disease; in vivo; insight; neoplastic cell; novel; response; selective expression; tumor

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.

描述（申请人提供）：转移性肾细胞癌（RCC）对大多数常规癌症治疗的反应较差，但在10-20%接受非特异性免疫治疗（如白细胞介素-2或干扰素-β）的患者中观察到转移性RCC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。全身给予细胞因子疗法的抗肿瘤作用尚未完全了解，但认为其增强了能够识别RCC肿瘤的宿主细胞免疫应答。然而，RCC细胞上缺乏合适的靶抗原，阻碍了RCC特异性免疫治疗的发展。最近，降低强度的异基因造血细胞移植（HCT）作为一种新形式的过继性免疫治疗转移性RCC的试点研究报告部分或完全的肿瘤反应，在一个子集的患者以这种方式治疗。反应通常在HCT后几个月观察到，在完全供体T细胞植入后，并且与移植物抗宿主病的发展密切相关，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）抗原的同种异体反应性T细胞在这种情况下介导移植物抗肿瘤效应。本申请中提供的数据表明，定义在RCC肿瘤细胞上表达的多种不同次要H抗原的CD 8+细胞毒性T淋巴细胞（CTL）克隆可以从在降低强度的同种异体HCT后经历肿瘤消退或稳定的RCC患者中分离。编码这些次要H抗原的基因的鉴定及其组织表达的表征可以鉴定用于免疫治疗的潜在靶点，并且可以为有效的抗肿瘤免疫应答的要求提供有价值的见解。该申请包括实验室和临床研究，旨在开发针对RCC肿瘤上次要H抗原的特异性免疫疗法。具体目标是： 1.鉴定编码小H抗原的基因，这些小H抗原被从接受同种异体HCT治疗的RCC患者中分离的RCC反应性CD 8 + CTL克隆识别，并定量其在正常和恶性组织中的表达。 2.评估过继转移的RCC反应性T细胞克隆在转移性RCC患者中的安全性、体内持久性和抗肿瘤疗效。 晚期肾癌（肾细胞癌）目前可用的治疗选择有限。异基因干细胞移植是一种独特的免疫治疗形式，对某些肾癌患者有效。确定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这种癌症的新型和更有效的免疫疗法的发展。