Anti-CD20 CTL for Therapy of Mantle Cell Lymphoma

描述（由申请人提供）：在美国，每年诊断出超过55,000例新发非霍奇金淋巴瘤（NHL），它是美国第五大常见癌症死亡原因。最近的流行病学数据表明，除恶性黑色素瘤外，该病发病率的增长速度比任何其他癌症都要快。套细胞淋巴瘤（MCL）是一种独立的实体，其生存期是所有NHL类型中最差的（中位2-3年）。大多数权威人士认为，传统的化疗和放疗方案不能治愈晚期MCL。本研究计划的目的是开展一项试验性I期临床试验，测试一种新的MCL免疫治疗方法，该方法使用经过基因修饰的自体T淋巴细胞，表达一种嵌合T细胞受体，识别B细胞淋巴瘤上的CD20抗原。在Aim 1中，我们将评估细胞免疫疗法对复发性CD20+ MCL患者的安全性、可行性和毒性，利用体外扩增的自体细胞毒性T细胞进行基因修饰，表达CD20特异性scFvFc:zeta嵌合免疫受体，该受体包含SP163翻译增强子以及CD28和CD137共刺激结构域。在T细胞输注之前，患者将使用氟达拉滨对内源性T细胞进行“淋巴耗损”，以促进过继转移的、经过基因修饰的cd20特异性T细胞的“稳态增殖”。在Aim 2中，我们将确定过继转移的cd20特异性T细胞在体内持续的时间以及它们向淋巴结和其他肿瘤部位的运输。在输注111铟标记的转基因抗cd20特异性T细胞后，将进行连续定量伽马相机成像。此外，流式细胞术和定量PCR将用于监测输注T细胞在血液和肿瘤部位的持久性，通过骨髓和LN活检。在Aim 3中，我们将监测在接受过继T细胞免疫治疗的患者中，针对抗cd20嵌合T细胞受体和NeoR选择基因产物产生的体液和细胞免疫反应的发展。迄今为止获得的初步结果表明，这种新的免疫疗法对复发的MCL患者来说是一种安全、有希望的方法。

DESCRIPTION (provided by applicant): More than 55,000 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed each year in the United States, and it is the fifth most common cause of cancer death in the United States. Recent epidemiological data demonstrate that the incidence of this disease is increasing more rapidly than any other cancer except malignant melanoma. Mantle cell lymphoma (MCL) is a discrete entity that has the worst survival of any type of NHL (median 2-3 years). Most authorities believe that conventional chemotherapy and radiation regimens are not curative for advanced MCL. The objective of this research proposal is to conduct a pilot Phase I clinical trial testing a novel new immunotherapeutic approach for MCL using autologous T lymphocytes that have been genetically modified to express a chimeric T cell receptor recognizing the CD20 antigen present on B cell lymphomas. In Aim 1, we will assess the safety, feasibility, and toxicity of cellular immunotherapy in patients with relapsed CD20+ MCL utilizing ex-vivo expanded, autologous cytotoxic T cells genetically modified to express a CD20-specific scFvFc:zeta chimeric immunoreceptor that incorporates an SP163 translational enhancer as well as CD28 and CD137 co-stimulatory domains. Before T cell infusions, patients will undergo "lymphodepletion" of endogenous T cells with fludarabine to promote "homeostatic proliferation" of the adoptively transferred, genetically-modified CD20-specific T cells. In Aim 2, we will determine the duration of in vivo persistence of adoptively transferred CD20-specific T cells and their trafficking to lymph nodes and other tumor sites. Serial quantitative gamma camera imaging will be performed after infusion of 111lndium-tagged, genetically modified, anti-CD20 specific T cells. In addition, serial flow cytometry and quantitative PCR will be employed to monitor the persistence of infused T cells in the bloodstream and in tumor sites using bone marrow and LN biopsies. In Aim 3, we will monitor the development of humoral and cellular immune responses generated against the anti-CD20 chimeric T cell receptor and the NeoR selection gene product in patients undergoing adoptive T cell immunotherapy. The preliminary results obtained to date suggest that this novel immunotherapy represents a safe, promising approach for patients with relapsed MCL.