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％的患有急性淋巴细胞白血病的成年人中，白血病细胞仍然存在，尽管进行了强化化疗，但经常导致致命的复发。提出的研究的基础假设是免疫细胞，即T淋巴细胞和天然杀伤（NK）细胞，通过遗传工程（“嵌合”）抗原受体重定向，可以消除全部抗药性药物。在初步研究中，识别CD19的受体（在所有细胞中高度表达的分子，除B淋巴细胞以外的所有正常细胞中都没有）向免疫细胞传递刺激信号，从而导致对CD19+所有细胞的强大细胞毒性。具体目的1是鉴定NK细胞中诱导最大膨胀和抗CD19细胞毒性的刺激信号分子。这些研究源于这样的观察，即NK细胞中抗CD19受体的表达绕过抑制性机制，并赋予抗所有细胞毒性，并依靠一种新方法来有效地将受体转导NK细胞中。结果应导致对全部难治性患者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使用。特定目标2中的研究将确定表达抗CD19受体的免疫细胞是否可以在白血病的异构鼠模型中根除所有。 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的抗原的注入细胞的有效性。如果有希望的话，结果应该为抗药性所有患者的受体改性自体和同种异体免疫细胞的临床测试提供强大的理由。具体目的3是增加受体改性免疫细胞的临床安全性。将开发允许同时表达受体和CD20的基因构建体，以使转导的细胞易于易受细胞毒性，这是由利妥昔单抗介导的，这是一种抗CD20抗体，在临床上使用。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将在体外和体内进行测试。嵌合受体指导的免疫疗法是癌症研究的新兴领域。该研究提出的不仅应刺激难治性患者的免疫细胞的临床研究，还应促进其他肿瘤的有效细胞疗法的发展。