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（由申请人提供）：在大约 20% 的患有急性淋巴细胞白血病 (ALL) 的儿童和 65% 的成人中，尽管进行了强化化疗，但白血病细胞仍持续存在，常常导致致命的复发。该研究提出的假设是，通过基因工程（“嵌合”）抗原受体重新定向的免疫细胞，即 T 淋巴细胞和自然杀伤 (NK) 细胞，可以根除耐药性 ALL。在初步研究中，识别 CD19（一种在 ALL 细胞中高度表达的分子，在除 B 淋巴细胞外的所有正常细胞中都不存在）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性。具体目标 1 是鉴定诱导 NK 细胞最大扩增和抗 CD19 细胞毒性的刺激信号分子。这些研究源于这样的观察：NK 细胞中抗 CD19 受体的表达绕过抑制机制并赋予抗 ALL 细胞毒性，并依赖于一种有效转导 NK 细胞中受体的新方法。这些结果应该会导致对难治性 ALL 患者的 NK 细胞进行临床研究，并可能扩大这些细胞在癌症治疗中的临床应用。具体目标 2 的研究将确定表达抗 CD19 受体的免疫细胞是否可以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 共刺激的潜在益处以及针对两种不同白血病相关抗原输注细胞的有效性。如果有希望，这些结果将为耐药 ALL 患者的受体修饰自体和同种异体免疫细胞的临床测试提供强有力的依据。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 同时表达的基因构建体，以努力使转导细胞对利妥昔单抗（一种临床使用的抗 CD20 抗体）介导的细胞毒性敏感。用这些构建体转导的 T 细胞和 NK 细胞的功能及其对利妥昔单抗的敏感性将在体外和体内进行测试。嵌合受体定向免疫疗法是癌症研究的一个新兴领域。拟议的研究不仅应该促进难治性 ALL 患者免疫细胞的临床研究，而且还有助于开发针对其他肿瘤的有效细胞疗法。