Anti-CTLA-4 Monoclonal Antibody Therapy for Lymphoma

描述（由申请方提供）：滤泡性B细胞非霍奇金淋巴瘤（NHL）可被认为是最“免疫应答”的人类癌症，这是基于其在使用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自发消退和显著应答率的能力。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细胞的扩增和效应子功能。逆转T细胞对肿瘤的低反应性的一种新方法是阻断负性T细胞调节分子细胞毒性T淋巴细胞抗原4（CTLA-4）。阻断性抗CTLA-4单克隆抗体的给药可在多种鼠肿瘤模型中促进抗肿瘤免疫。在最近的几项I期临床试验中，利用抗CTLA-4单克隆抗体对抗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细胞淋巴瘤对免疫干预的独特易感性，我们假设抗CTLA-4在这种疾病背景下应该具有显著的临床活性，并且可能增加其他淋巴瘤免疫疗法如疫苗的功效。因此，我们提出了一项新的临床试验，将有助于建立适当的给药方案，毒性特征，抗CTLA-4单药活性的B细胞淋巴瘤患者。 具体目标1。进行I/II期临床试验，以表征抗CTLA-4单克隆抗体在滤泡B细胞非霍奇金淋巴瘤患者中的安全性和临床疗效。这项多中心研究（加州大学洛杉矶分校和马约诊所）将包括多达36例可测量的滤泡性淋巴瘤复发后或耐常规治疗。既往接受过肿瘤疫苗接种的患者将占受试者的一半。 具体目标2。确定抗CTLA-4治疗是否导致滤泡性淋巴瘤患者抗肿瘤免疫效应机制的全身募集。在治疗之前和之后，将对外周血进行采样以测量：1）肿瘤特异性细胞因子释放和细胞毒性，2）记忆T细胞对回忆抗原刺激的响应性，3）循环T细胞的数量和活化状态，包括组成性表达CTLA-4的CD 4 + CD 25+调节性T细胞群，和4）肿瘤特异性抗体。 具体目标3。研究抗CTLA-4治疗是否可以增加肿瘤微环境中T细胞效应器的数量和功能。将在治疗前和治疗后对肿瘤进行活检，以表征肿瘤浸润淋巴细胞亚群（包括CD 4+、CD 8+和CD 4 + CD 25+调节性T细胞）的数量和活化状态，并评价肿瘤浸润T细胞在体外扩增后的抗肿瘤作用。

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.