Anti-CTLA-4 Monoclonal Antibody Therapy for Lymphoma

抗 CTLA-4 单克隆抗体治疗淋巴瘤

• 批准号: 6950284
• 负责人: John M Timmerman
• 金额: $ 25.34万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-18 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950284
• 关键词: CD28 molecule; biopsy; clinical research; clinical trial phase I; clinical trial phase II; cytotoxic T lymphocyte; cytotoxicity; dosage; human subject; human therapy evaluation; immunotherapy; monoclonal antibody; neoplasm /cancer vaccine; nonHodgkin' s lymphoma; patient oriented research; therapy design /development

DESCRIPTION (provided by applicant): Follicular B cell non-Hodgkin's lymphoma (NHL) can be considered the most "immune-responsive" of human cancers based on its capacity for spontaneous regression and substantial response rate following treatment with non-specific immunostimulants, monoclonal antibodies, and therapeutic tumor vaccines. Despite this, tumor immune-escape and physiologic T cell homeostasis mechanisms appear to limit the expansion and effector functions of potentially tumor-reactive T cells. One novel approach to the reversal of T cell hyporesponsiveness towards tumors is blockade of the negative T cell regulatory molecule cytotoxic T lymphocyte antigen 4 (CTLA-4). Administration of blocking anti-CTLA-4 monoclonal antibodies can promote anti-tumor immunity in a wide variety of murine tumor models. Promising clinical activity has been observed in several recent phase I clinical trials utilizing anti-CTLA-4 monoclonal antibodies against melanoma and prostate cancer. Given the unique susceptibility of B cell lymphoma to immunotherapeutic interventions, we hypothesize that anti-CTLA-4 should have significant clinical activity in this disease setting, and could possibly augment the efficacy of other lymphoma immunotherapies such as vaccines. We therefore propose a new clinical trial that will serve to establish the appropriate dosing schedule, toxicity profile, and single agent activity of anti-CTLA-4 in B cell lymphoma patients. Specific Aim 1. Perform a phase I/II clinical trial to characterize the safety and clinical efficacy of anti-CTLA-4 monoclonal antibody in patients with follicular B cell non-Hodgkin's lymphoma. This multi-center study (UCLA & Mayo Clinic) will include up to 36 patients with measurable follicular lymphoma relapsing after or resistant to conventional therapies. Patients who have received prior tumor vaccines will represent one-half of subjects. Specific Aim 2. Determine whether anti-CTLA-4 treatment results in systemic recruitment of anti-tumor immune effector mechanisms in patients with follicular lymphoma. Before and after therapy, peripheral blood will be sampled for measurement of: 1) Tumor-specific cytokine release and cytotoxicity, 2) Responsiveness of memory T cells to stimulation with recall antigens, 3) The numbers and activation state of circulating T cells, including the CD4+CD25+ regulatory T cell population which constitutively expresses CTLA-4, and 4) Tumor-specific antibodies. Specific Aim 3. Investigate whether anti-CTLA-4 therapy can boost number and function of T cell effectors in the tumor microenvironment. Tumors will be biopsied pre- and post-treatment to characterize the number and activation state of tumor infiltrating lymphocyte subpopulations (including CD4+, CD8+, and CD4+CD25+ regulatory T cells), and to evaluate the anti-tumor effects of tumor infiltrating T cells following in vitro expansion.

描述（由申请人提供）：基于非特异性接触剂，单支抗体抗体和治疗剂，基于其自发回归和实质性缓解率，​​可以将卵泡B细胞非霍奇金淋巴瘤（NHL）视为人类癌的最“免疫反应性”。尽管如此，肿瘤免疫escape和生理T细胞稳态机制似乎限制了潜在的肿瘤反应性T细胞的膨胀和效应子功能。 T细胞逆转对肿瘤的逆转的一种新型方法是阻断T细胞调节分子细胞毒性T淋巴细胞抗原4（CTLA-4）的封锁。抑制抗CTLA-4单克隆抗体可以促进多种鼠肿瘤模型中的抗肿瘤免疫。使用抗CTLA-4单克隆抗体和前列腺癌的抗CTLA-4单克隆抗体，在最近的几项I期临床试验中观察到了有希望的临床活性。鉴于B细胞淋巴瘤对免疫治疗干预的独特敏感性，我们假设抗CTLA-4在这种疾病环境中应具有重要的临床活性，并且可能会增加其他淋巴瘤免疫疗法（如疫苗）的疗效。因此，我们提出了一项新的临床试验，该试验将建立适当的给药时间表，毒性特征和抗CTLA-4在B细胞淋巴瘤患者中的单一药物活性。 具体目标1。执行I/II期临床试验，以表征抗CTLA-4单克隆抗体对卵泡B细胞非霍奇金淋巴瘤患者的安全性和临床功效。这项多中心研究（UCLA＆Mayo诊所）将包括36例可测量的卵泡淋巴瘤患者，或者对常规疗法有抵抗力。接受过肿瘤疫苗的患者将代表一半受试者。 具体目标2。确定抗CTLA-4治疗是否导致卵泡淋巴瘤患者的抗肿瘤免疫效应机制的全身募集。治疗前后，将对外周血进行测量：1）肿瘤特异性细胞因子释放和细胞毒性，2）记忆T细胞对用回忆抗原刺激的反应性，3）3）循环T细胞的数量和激活状态，包括CD4+ CD25+ CD25+ CD25+ CD25+ CD25+调节性T细胞群，这些cd25+ cd25+ CD25+ cdib sprificience contecibific thumeratific thumer contecific thumor contec tula tum c.tla-4 and 4）和4）和4）。 具体目的3。研究抗CTLA-4治疗是否可以增加肿瘤微环境中T细胞效应子的数量和功能。肿瘤将进行活检前和治疗后，以表征肿瘤浸润的淋巴细胞亚群的数量和激活状态（包括CD4+，CD8+和CD4+CD4+CD25+调节性T细胞），并评估肿瘤渗透T细胞的抗肿瘤效应。