CHECKPOINT BLOCKADE IN IMMUNOTHERAPY OF PROSTATE CANCER

前列腺癌免疫治疗中的检查点封锁

• 批准号: 8555198
• 负责人: JAMES P ALLISON
• 金额: $ 13.48万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-14 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555198
• 关键词: Aftercare; Androgen Receptor; Antibodies; Antibody Formation; Antigens; Autoimmune Responses; Biological Assay; CD28 gene; CTAG1 gene; Cancer Model; Castration; Cell physiology; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Cryosurgery; Data; Development; Disease; Disease regression; Failure; Family; Family member; Homeostasis; Immune; Immune response; Immunologic Monitoring; Immunotherapy; In Vitro; Interleukin-2; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Measurable; Measures; Metastatic Melanoma; Modeling; Monoclonal Antibodies; Mus; Outcome; Pathway interactions; Patients; Phase; Phase III Clinical Trials; Phosphotransferases; Pre-Clinical Model; Prostatic Neoplasms; Radiation therapy; Reproduction spores; Resistance; Resistance development; Role; Sampling; Serum; Signal Pathway; T-Cell Activation; T-Lymphocyte; Testing; Translating; Tumor Antigens; Wild Type Mouse; chemotherapy; high risk; immune function; improved; inhibitor/antagonist; neoplastic cell; pre-clinical; prevent; response; success; therapy resistant; tumor

Blockade of inhibitory molecules on T cells has been shown to be an effective Immunotherapy strategy to treat cancer. The prototypic inhibitory molecule is CTLA-4, which is induced upon T cell activation and acts to inhibit proliferation. We hypothesized that although CTLA-4 is necessary to maintain homeostasis and prevent autoimmune responses, it might also limit effective anti-tumor immune responses. We developed anti-CTLA-4 and used it to successfully treat tumors in murine models. Our data were translated to the clinic and a phase 3 trial with anti-CTLA-4 was recently shown to lead to durable regression of disease and survival benefit in some patients with metastatic melanoma. Because anti-CTLA-4 therapy is not tumor specific, and phase 1 and 2 clinical trials have demonstrated a clinical response in patients with prostate cancer, a phase 3 clinical trial is currently accruing patients with metastatic castration-resistant prostate cancer (CRPC). Our specific aims are as follows: 1. To determine the effects of immune checkpoint blockade and targeted therapies on immune function and anti-tumor responses, a) To determine quantitative changes in immune cell subpopulations of wild-type mice following treatment, b) To determine changes in antigen-specific T cell functions using adoptive T cell transfer, c) To optimize anti-tumor responses in murine prostate cancer models using combinations of targeted therapy and immune checkpoint blockade. 2. To determine the role of sB7-H3 and sB7-H4 in prostate cancer, a) To assay patient serum samples for SB7-H3 and sB7-H4 and correlate levels with disease status, b) To determine the immunomodulatory effects of SB7-H4 in vitro. 3. To determine whether CTLA-4 blockade in CRPC results in detectable immunological changes that correlate with clinical outcomes, a) To assess antibody responses against tumor antigens in treated patients, b) To assess ICOS (inducible co-stimulator) expression on T cells in treated patients, c) To assess serum levels of SB7-H3

阻断T细胞上的抑制分子已被证明是一种有效的免疫治疗策略 治疗癌症。典型的抑制分子是CTLA-4，它是在T细胞激活后诱导并发挥作用的 以抑制其增殖。我们假设，尽管CTLA-4对于维持体内平衡和 在阻止自身免疫反应的同时，它也可能限制有效的抗肿瘤免疫反应。我们开发了 抗CTLA-4，并将其成功地用于治疗小鼠模型的肿瘤。我们的数据被转移到了诊所 抗CTLA-4的3期试验最近被证明导致疾病的持久消退和 一些转移性黑色素瘤患者的生存受益。因为抗CTLA-4治疗不是肿瘤 1期和2期临床试验已证实前列腺癌患者的临床反应。 癌症，一项3期临床试验目前正在招募耐去势转移性前列腺癌患者 癌症(CRPC)。我们的具体目标如下： 1.确定免疫关卡阻断和靶向治疗对免疫功能和 抗肿瘤反应，a)确定野生型小鼠免疫细胞亚群的数量变化 治疗后，b)使用过继T细胞确定抗原特异性T细胞功能的变化 Transfer，c)使用以下组合优化小鼠前列腺癌模型的抗肿瘤反应 靶向治疗和免疫检查站封锁。 2.为了确定SB7-H3和SB7-H4在前列腺癌中的作用，a)检测患者血清样本 SB7-H3和SB7-H4，并与疾病状态相关，b)确定免疫调节作用 SB7-H4的体外活性。 3.确定在CRPC中阻断CTLA-4是否导致可检测到的免疫学变化 与临床结果相关，a)评估治疗患者对肿瘤抗原的抗体反应， B)评估接受治疗的患者T细胞上ICOS(诱导型共刺激因子)的表达，c)评估血清 SB7-H3水平