Cell Therapy of Refractory Leukemia

难治性白血病的细胞疗法

• 批准号: 7039384
• 负责人: DARIO CAMPANA
• 金额: $ 28.55万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039384
• 关键词: CD antigens; CD19 molecule; NOD mouse; SCID mouse; T lymphocyte; acute lymphocytic leukemia; antigen receptors; biological signal transduction; bone marrow; chimeric proteins; clinical research; cytotoxicity; disease /disorder model; drug resistance; gene therapy; human subject; monoclonal antibody; natural killer cells; neoplasm /cancer immunotherapy; pediatric neoplasm /cancer; therapy design /development; tissue /cell culture; xenotransplantation

DESCRIPTION (provided by applicant): In approximately 20% of children and 65% of adults with acute lymphoblastic leukemia (ALL), leukemic cells persist despite intensive chemotherapy, leading to often fatal relapse. The hypothesis underlying the research proposed is that immune cells, i.e., T lymphocytes and natural killer (NK) cells, redirected by genetically-engineered ("chimeric") antigen receptors can eradicate drug-resistant ALL. In preliminary studies, receptors that recognize CD19 (a molecule highly expressed in ALL cells and absent in all normal cells except B lymphocytes) deliver stimulatory signals to immune cells resulting in powerful cytotoxicity against CD19+ ALL cells. Specific Aim 1 is to identify stimulatory signaling molecules that induce maximum expansion and anti-CD19 cytotoxicity in NK cells. These studies stem from the observation that expression of anti-CD19 receptors in NK cells bypasses inhibitory mechanisms and confers anti-ALL cytotoxicity, and rely on a novel method to efficiently transduce the receptors in NK cells. The results should lead to clinical studies of NK cells in patients with refractory ALL and may expand the clinical use of these cells in cancer therapy. Studies in Specific Aim 2 will determine whether immune cells expressing anti-CD19 receptors can eradicate ALL in xenogeneic murine models of leukemia. The relative anti-leukemic capacity of NK cells and T cells, the potential benefits of 4-1BB and CD28 co-stimulation, and the effectiveness of infusing cells directed against two different leukemia-associated antigens will be assessed. If promising, the results should provide a strong rationale for clinical testing of receptor-modified autologous and allogeneic immune cells in patients with drug-resistant ALL. Specific Aim 3 is to increase the clinical safety of receptor-modified immune cells. Gene constructs that allow simultaneous expression of the receptors and of CD20 will be developed in efforts to render transduced cells susceptible to cytotoxicity mediated by Rituximab, an anti-CD20 antibody used clinically. The function of T and NK cells transduced with these constructs and their sensitivity to Rituximab will be tested in vitro and in vivo. Chimeric receptor-directed immunotherapy is an emerging area of cancer research. The research proposed should not only spur clinical studies of immune cells in patients with refractory ALL but also facilitate the development of effective cell therapies for other neoplasms.

描述(申请人提供)：在大约20%的儿童急性淋巴细胞白血病(ALL)和65%的成人急性淋巴细胞白血病(ALL)中，尽管进行了密集的化疗，白血病细胞仍然存在，导致往往致命的复发。这项研究提出的假设是，免疫细胞，即T淋巴细胞和自然杀伤(NK)细胞，由基因工程(“嵌合”)抗原受体重定向，可以根除耐药ALL。在初步研究中，识别CD19的受体向免疫细胞传递刺激信号，从而对CD19+ALL细胞产生强大的细胞毒作用。CD19是一种在所有细胞中都高表达，但在所有正常细胞中都不表达的分子。特异的目的1是鉴定在NK细胞中最大限度地诱导扩增和抗CD19细胞毒的刺激信号分子。这些研究源于观察到NK细胞中抗CD19受体的表达绕过了抑制机制并具有抗ALL的细胞毒作用，并依赖于一种新的方法来有效地转导NK细胞中的受体。这一结果将导致难治性ALL患者的NK细胞的临床研究，并可能扩大这些细胞在癌症治疗中的临床应用。针对特定目标2的研究将确定表达抗CD19受体的免疫细胞是否能够根除异种小鼠白血病模型中的ALL。将评估NK细胞和T细胞的相对抗白血病能力，4-1BB和CD28共同刺激的潜在益处，以及针对两种不同白血病相关抗原的输注细胞的有效性。如果前景看好，这些结果将为临床测试耐药ALL患者的受体修饰的自体和同种异体免疫细胞提供强有力的理论基础。具体目标3是提高受体修饰免疫细胞的临床安全性。将开发允许受体和CD20同时表达的基因结构，以使转导细胞对临床使用的抗CD20抗体利妥昔单抗介导的细胞毒性敏感。用这些载体转导的T细胞和NK细胞的功能以及它们对利妥昔单抗的敏感性将在体外和体内进行测试。嵌合受体导向免疫治疗是癌症研究的一个新兴领域。提出的这项研究不仅应该促进难治性ALL患者免疫细胞的临床研究，还将促进其他肿瘤有效细胞疗法的发展。