T CELL COSTIMULATION IN ANTITUMOR RESPONSES

T 细胞共刺激在抗肿瘤反应中的作用

• 批准号: 6171918
• 负责人: JAMES P ALLISON
• 金额: $ 22.83万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-20 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171918
• 关键词: autoimmunity; breast neoplasms; colon neoplasms; cytotoxic T lymphocyte; gene therapy; immunomodulators; kidney neoplasms; laboratory mouse; laboratory rat; leukocyte activation /transformation; melanoma; monoclonal antibody; natural killer cells; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer transplantation; prostate neoplasms; tissue /cell culture

The main goal of tumor immunotherapy Is to obtain tumor specific T cell responses capable of eradicating disseminated disease and providing protection against recurrence. Recent advances in our knowledge mechanisms of T cell activation have aided In the design of rational strategies to obtain this goal. One particularly significant advance has been the realization that T cell activation requires costimulary signals mediated by CD28 in addition to antigen-specific signals, and that tumor cells do not provide costimulation. This has led to strategies of lmmunotherapy that manipulate costimulation, such as induction of expression the costimulatory ligand B7 or enhancement of tumor antigen presentation by costimulation competent host antigen presenting cells. However, it has recently been demonstrated that T cell responses are negatively regulated by CTLA-4. We have demonstrated that blockade of the inhibitory signals of CTLA-4 can greatly enhance antitumor responses. We now propose to extend these studies and: 1.Determine the effectiveness of CTLA-4 blockade,alone and in combination with other immunomodulatory agents in subcutaneous tumor models that represent a spectrum of Inherent immunogeniclty and have relevance to models of metastasis and primary tumors. The effectiveness of CTLA-4 will be assessed by itself and in combination with other immunomodulatory agents that rely on costimulation, including B7, GM-CSF, and antigen-pulsed dendritic cells. Treatment protocols will be compared with respect to effectiveness in eradication of established tumors and longevity of protection to tumor rechallenge. 2.Determine the effectiveness of optimized protocols Involving CTLA-4 blockade in the treatment of experimental metastases, using models for melanoma, renal carcinoma, and prostatic carcinoma. 3.Determine the effectiveness of optimized protocols for involving CTLA- blockade in the treatment and prevention of primary tumors. 4.Examine the mechanisms involved in enhancement of antitumor immunity by protocols involving CTLA-4 blockade. We will identify lymphocytes involved in rejection and in induction of immunity, determine the effects on relative contributions of the tumor cells and host cells in antigen presentation, and test the hypothesis that CTLA- 4 blockade reveals normally silent tumor epitopes. 5.Examine the possibility that autoimmunity might accompany tumor rejection induced by CTLA-4 blockade.

肿瘤免疫治疗的主要目标是获得肿瘤特异性 T细胞反应能够根除播散性疾病， 提供防止复发的保护。我们的最新进展 T细胞激活的知识机制有助于设计 理性的策略来实现这个目标。一个特别重要的 研究人员已经认识到，T细胞活化需要 CD 28介导的共刺激信号，除了抗原特异性 信号，并且肿瘤细胞不提供共刺激。这 导致了操纵共刺激的免疫治疗策略， 例如诱导共刺激配体B7的表达，或 共刺激增强肿瘤抗原提呈 感受态宿主抗原呈递细胞。但近来 已经证明，T细胞反应是负调控的， CTLA-4我们已经证明， CTLA-4的信号可以大大增强抗肿瘤反应。我们 现在建议扩大这些研究，并： 1.确定CTLA-4阻断剂单独和联合应用的有效性。 与其他免疫调节剂联合皮下给药 代表一系列固有免疫原性的肿瘤模型 并且与转移和原发肿瘤的模型相关。的 CTLA-4的有效性将由其本身进行评估， 与其他依赖于 共刺激，包括B7、GM-CSF和抗原脉冲树突状细胞 细胞治疗方案将在以下方面进行比较 有效根除已建立的肿瘤和长寿的 对肿瘤再激发的保护作用。 2.确定优化方案的有效性 CTLA-4阻断治疗实验性转移瘤，使用 用于黑素瘤、肾癌和前列腺癌的模型。 3.确定优化方案的有效性， CTLA-阻断在原发性肿瘤的治疗和预防中的应用。 4.检查参与增强抗肿瘤作用的机制 通过涉及CTLA-4阻断的方案获得免疫力。我们将确定 参与排斥和免疫诱导的淋巴细胞， 确定对肿瘤细胞的相对贡献的影响， 宿主细胞的抗原呈递，并测试假设，CTLA- 4阻断揭示了正常沉默的肿瘤表位。 5.探讨自身免疫与肿瘤的可能性 CTLA-4阻断诱导的排斥反应。