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%的儿童和65%的成人急性淋巴细胞白血病（ALL）中，尽管进行了强化化疗，白血病细胞仍然存在，导致经常致命的复发。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CD 19（一种在ALL细胞中高度表达且在除B淋巴细胞外的所有正常细胞中不存在的分子）的受体向免疫细胞递送刺激信号，导致对CD 19 + ALL细胞的强大细胞毒性。具体目标1是鉴定在NK细胞中诱导最大扩增和抗CD 19细胞毒性的刺激信号分子。这些研究源于观察到NK细胞中抗CD 19受体的表达绕过抑制机制并赋予抗ALL细胞毒性，并依赖于一种新的方法来有效地抑制NK细胞中的受体。这些结果将导致NK细胞在难治性ALL患者中的临床研究，并可能扩大这些细胞在癌症治疗中的临床应用。特定目标2研究将确定表达抗CD 19受体的免疫细胞是否可以在白血病异种小鼠模型中根除ALL。将评估NK细胞和T细胞的相对抗白血病能力、4-1BB和CD 28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。如果有希望的话，这些结果应该为耐药ALL患者中受体修饰的自体和同种异体免疫细胞的临床试验提供强有力的理论基础。具体目标3是增加受体修饰的免疫细胞的临床安全性。将开发允许受体和CD 20同时表达的基因构建体，以使转导细胞对利妥昔单抗（一种临床使用的抗CD 20抗体）介导的细胞毒性敏感。将在体外和体内测试用这些构建体转导的T和NK细胞的功能及其对利妥昔单抗的敏感性。嵌合受体介导的免疫治疗是癌症研究的一个新兴领域。这项研究不仅可以促进难治性ALL患者免疫细胞的临床研究，还可以促进其他肿瘤有效细胞疗法的发展。