Anti-CTLA-4 Monoclonal Antibody Therapy for Lymphoma

描述（由申请人提供）：滤泡性B细胞非霍奇金淋巴瘤（NHL）可被认为是人类癌症中最具“免疫应答性”的癌症，基于其在非特异性免疫刺激剂、单克隆抗体和治疗性肿瘤疫苗治疗后的自发消退能力和可观的应答率。尽管如此，肿瘤免疫逃逸和生理性T细胞稳态机制似乎限制了潜在肿瘤反应性T细胞的扩张和效应功能。一种逆转T细胞对肿瘤低反应性的新方法是阻断负T细胞调节分子细胞毒性T淋巴细胞抗原4 （CTLA-4）。阻断抗ctla -4单克隆抗体可促进多种小鼠肿瘤模型的抗肿瘤免疫。在最近的几项I期临床试验中，利用抗ctla -4单克隆抗体治疗黑色素瘤和前列腺癌已经观察到有希望的临床活性。鉴于B细胞淋巴瘤对免疫治疗干预的独特易感性，我们假设抗ctla -4在这种疾病中应该具有显著的临床活性，并且可能增强其他淋巴瘤免疫疗法（如疫苗）的疗效。因此，我们建议进行一项新的临床试验，以确定B细胞淋巴瘤患者中抗ctla -4的适当给药计划、毒性特征和单药活性。

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.