Cell Therapy of Refractory Leukemia

难治性白血病的细胞疗法

• 批准号: 7531803
• 负责人: DARIO CAMPANA
• 金额: $ 28.96万
• 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/7531803
• 关键词: Acute Lymphocytic Leukemia; Adult; Allogenic; Antigen Receptors; Antigens; Area; Autologous; B-Lymphocytes; Bone Marrow; Bypass; CD19 gene; CD20 Antigens; CD28 gene; Cell Culture Techniques; Cell Line; Cell Therapy; Cells; Child; Clinical; Clinical Research; Clinical Trials; Development; Donor person; Drug resistance; Effectiveness; Engineering; Engraftment; Genes; HLA Antigens; Hematopoietic stem cells; Immune; Immunotherapy; Insertional Mutagenesis; Intervention; Lead; Leukemic Cell; MS4A1 gene; Mediating; Mesenchymal; Methods; Modeling; Mus; Natural Killer Cells; Neoplasms; Normal Cell; Organ; Patients; Refractory; Relapse; Relative (related person); Research; Research Personnel; Retroviral Vector; Risk; Safety; Signal Transduction; Signaling Molecule; Stem cell transplant; System; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; Testing; Tissues; Toxic effect; Translations; anticancer research; cancer therapy; cellular transduction; chemotherapy; cytotoxicity; in vitro testing; in vivo; leukemia; novel; programs; receptor; receptor expression; research clinical testing; rituximab; stem; tositumomab

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 T.he 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-IBB 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.

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（全），白血病 尽管进行了强化化疗，但细胞仍然持续，导致致命的复发。基础的假设 研究提出的是免疫细胞，即T淋巴细胞和天然杀伤（NK）细胞，由 遗传工程（“嵌合”）抗原受体可以消除所有抗药性。在初步 研究，识别CD19的受体（在所有细胞中高度表达的分子，在所有正常情况下都不存在 除B淋巴细胞以外的细胞）向免疫细胞传递刺激信号，从而产生强大的细胞毒性 针对CD19+所有细胞。 特定目的1是鉴定诱导最大膨胀和抗CD19的刺激信号传导分子 NK细胞中的细胞毒性。这些研究源于T.他观察到抗CD19受体在 NK细胞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 有效地将受体转导NK细胞。结果应导致NK细胞中的临床研究 难治性的患者全部可以扩大这些细胞在癌症治疗中的临床使用。研究 具体目标2将确定表达抗CD19受体的免疫细胞是否可以根除所有 白血病的异构鼠模型。 NK细胞和T细胞的相对抗白血病能力， 4-ibb和CD28共刺激的潜在优势，以及针对针对的细胞的有效性 将评估两种不同的白血病相关抗原。如果有希望，结果应该提供强大的 对受体改性自体和同种异体免疫细胞的临床测试的理由 全部耐药。具体目的3是增加受体改性免疫细胞的临床安全性。基因 将开发允许同时表达受体和CD20的构造以努力 使转导的细胞易于利妥昔单抗介导的细胞毒性，这是一种抗CD20抗体 临床。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。研究提出了 不仅应刺激难治性患者免疫细胞的临床研究，还应促进 开发其他肿瘤的有效细胞疗法。