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例新的非霍奇金淋巴瘤（NHL）病例，并且它是美国癌症死亡的第五大常见原因。最近的流行病学数据表明，除了恶性黑色素瘤之外，这种疾病的发病率比任何其他癌症都增长得更快。套细胞淋巴瘤（MCL）是一种独立的实体，在任何类型的NHL中生存期最差（中位数2-3年）。大多数权威认为，常规化疗和放疗方案不能治愈晚期MCL。本研究提案的目的是进行一项试验性I期临床试验，使用经遗传修饰的自体T淋巴细胞检测MCL的新型免疫抑制方法，以表达识别B细胞淋巴瘤上存在的CD 20抗原的嵌合T细胞受体。在目标1中，我们将评估细胞免疫疗法在复发性CD 20 + MCL患者中的安全性、可行性和毒性，所述细胞免疫疗法使用经遗传修饰的离体扩增的自体细胞毒性T细胞，以表达CD 20特异性scFvFc：zeta嵌合免疫受体，所述嵌合免疫受体结合SP163翻译增强子以及CD 28和CD 137共刺激结构域。在T细胞输注之前，患者将用氟达拉滨进行内源性T细胞的“淋巴细胞清除”，以促进过继转移的遗传修饰的CD 20特异性T细胞的“稳态增殖”。在目标2中，我们将确定过继转移的CD 20特异性T细胞的体内持续时间及其向淋巴结和其他肿瘤部位的运输。在输注111铟标记的、遗传修饰的抗CD 20特异性T细胞后，将进行连续定量伽马相机成像。此外，将采用连续流式细胞术和定量PCR来监测输注的T细胞在血流中的持久性以及使用骨髓和LN活检的肿瘤部位。在目标3中，我们将监测在接受过继性T细胞免疫治疗的患者中针对抗CD 20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应答的发展。迄今为止获得的初步结果表明，这种新的免疫疗法代表了复发性MCL患者的安全，有前途的方法。

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.