Novel Cellular Therapies for Ph+ leukemia

治疗 Ph 白血病的新型细胞疗法

• 批准号: 7737278
• 负责人: HANS KLINGEMANN
• 金额: $ 70.71万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737278
• 关键词: Acute Myelocytic Leukemia; Adoptive Immunotherapy; Affect; Air; Allogenic; Allografting; Animals; Antibodies; Antigen Receptors; Antigens; Autologous; Autoradiography; B-Cell Acute Lymphoblastic Leukemia; Backcrossings; Blood; Blood Cells; Bone Marrow; Breeding; Budgets; Buffers; CD19 Antigens; CD19 gene; CD44 gene; Calendar; Categories; Cell Culture Techniques; Cell Line; Cells; Cellular biology; Censuses; Centrifugation; Charge; Chimera organism; Chromosomes; Chronic Myeloid Leukemia; Clinic; Clinical; Clinical Research; Contracts; Core Facility; Culture Media; DNA; DNA-Directed RNA Polymerase; Development; Direct Costs; Disease; Disease remission; Doctor of Philosophy; Dose; Drug Delivery Systems; Effectiveness; Employee; Employment; Engraftment; Equipment; Face; Facilities and Administrative Costs; Failure; Fees; Flow Cytometry; Fringe Benefit; Funding; Future; Generations; Genetic; Genotype; Goals; Grant; Guidelines; Health; Health Physics; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Homing; Hour; Human; Human Resources; Imatinib mesylate; Immune; Immune system; Immunodeficient Mouse; Immunology; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infusion procedures; Inpatients; Instruction; Interleukin-15; Interleukin-2; Interleukin-3; Interleukin-6; Joints; Knock-out; Knowledge; Laboratories; Laboratory mice; Left; Leukemic Cell; Life; Ligands; Luciferases; Lymphoblastic Leukemia; Lymphoid; Lymphoid Cell; MS4A1 gene; Maintenance; Malignant - descriptor; Malignant lymphoid neoplasm; Mediating; Medical center; Messenger RNA; Methods; Minor Histocompatibility Antigens; Modeling; Molecular; Molecular Biology; Molecular Immunology; Mus; Myeloproliferative disease; NOD/SCID mouse; Names; Natural Killer Cells; Outpatients; P-selectin ligand protein; Patient Care; Patients; Personnel Management; Pharmaceutical Preparations; Philadelphia Chromosome; Positioning Attribute; Postdoctoral Fellow; Preparation; Price; Principal Investigator; Procedures; Process; Publications; RNA; Radiation; Radiation Protection; Radioactivity; Radioisotopes; Reagent; Recruitment Activity; Relapse; Reporter; Research; Research Personnel; Residual Tumors; Residual state; Resistance; Role; Safety; Salaries and Fringe Benefits; Scientist; Selectins; Serum; Services; Shipping; Ships; Southern Blotting; Staging; Staining method; Stains; Stem cells; Students; Sum; T-Lymphocyte; Testing; Therapeutic Studies; Time; TimeLine; Transfection; Transfusion; Translating; Translations; Transplantation; Transportation; Travel; Treatment Protocols; Tumor Necrosis Factor Receptor; Tyrosine Kinase Inhibitor; Umbilical Cord Blood; Umbilical cord structure; United States National Institutes of Health; Vendor; Wages; Work; X-Ray Film; antibody-dependent cell cytotoxicity; base; bcr-abl Fusion Proteins; cancer cell; cellular engineering; cesium chloride; chemotherapy; clinically relevant; cost; cytokine; cytotoxic; design; efficacy testing; experience; fetal; graduate student; graft vs host disease; high risk; improved; in vivo; killings; leukemia; meetings; mouse model; mutant; novel; pre-clinical; programs; receptor; receptor expression; research study; response; restriction enzyme; retroviral transduction; therapy design; tissue culture; translational study; tyrosine kinase ABL1

The Philadelphia chromosome-positive (Ph+) leukemias, including chronic myeloid leukemia (CML) and Ph+ B- cell acute lymphoblastic leukemia (B-ALL), are prevalent blood cancers for which our current therapies are inadequate. While BCR-ABL tyrosine kinase inhibitors (TKIs) such as imatinib mesylate have replaced hematopoietic stem cell transplantation (HSCT) as initial therapy for CML, complete molecular remissions are rare and acquired resistance to TKI therapy is a significant clinical problem. Eligible Ph+ B-ALL patients undergo allogeneic HSCT in first remission following chemotherapy, but over half will relapse. Hence, it is likely that current therapy will not cure most Ph+ leukemia patients, and effective methods to eradicate residual leukemia are needed. This is a collaborative, dual-PI application from two senior clinician-scientists focused on the preclinical development of novel transfusion-based cellular therapies designed to eliminate residual disease in Ph+ leukemia patients, leading to permanent cure. To accomplish these goals, we will utilize a well- characterized mouse model of CML and Ph+ B-ALL to determine the efficacy and cellular mechanisms of adoptive immunotherapy with allogeneic T-lymphocytes or natural killer (NK) cells. To extend the benefits of NK cell immunotherapy to lymphoid malignancies, we will continue the preclinical development of NK cells engineered to express activating receptors that recognize ligands on B-lymphoid leukemia cells (CD19 and CD20), and test their efficacy in an in vivo immunotherapy model against human Ph+ B-ALL in NOD/SCID/¿c mice. Finally, having demonstrated that HSC in CML are uniquely dependent on selectins and their ligands for homing and engraftment in mice, we will develop clinically relevant methods for blocking engraftment of leukemic stem cells without affecting normal HSC. Throughout the application, a major emphasis will be placed on translation of novel findings to the clinic. Together, these studies should yield important new knowledge that will improve the effectiveness of adoptive immunotherapy and autologous HSCT for Ph+ leukemia, and increase the proportion of patients that are cured of their disease. PHS 398/2590 (Rev. 11/07) Page 2 Continuation Format Page Program Director/Principal Investigator (Last, First, Middle): Van Etten R.A./Klingemann H.K.

费城染色体阳性 (Ph+) 白血病，包括慢性粒细胞白血病 (CML) 和 Ph+ B- 细胞急性淋巴细胞白血病（B-ALL）是一种常见的血癌，我们目前的治疗方法是 而BCR-ABL酪氨酸激酶抑制剂（TKI）如甲磺酸伊马替尼已被取代。 造血干细胞移植（HSCT）作为 CML 的初始治疗，完全分子缓解 对 TKI 治疗的罕见和获得性耐药是符合条件的 Ph+ B-ALL 患者的一个重要临床问题。 化疗后第一次缓解时接受同种异体造血干细胞移植，但超过一半会复发，因此很可能会复发。 目前的疗法无法治愈大多数 Ph+ 白血病患者，以及根除残留的有效方法 这是一项由两位高级临床医生-科学家合作的双 PI 应用程序，重点关注白血病。 旨在消除残留的新型基于输血的细胞疗法的临床前开发 为实现这些目标，我们将利用一种良好的方法。 表征 CML 和 Ph+ B-ALL 小鼠模型，以确定其功效和细胞机制 使用同种异体 T 淋巴细胞或自然杀伤 (NK) 细胞的过继免疫疗法可延长其益处。 NK细胞免疫治疗淋巴恶性肿瘤，我们将继续NK细胞的临床前开发 设计用于表达识别 B 淋巴细胞白血病细胞（CD19 和 CD20），并在 NOD/SCID/¿ 中针对人 Ph+ B-ALL 的体内免疫治疗模型中测试其功效c 最后，证明 CML 中的 HSC 独特地依赖于选择素及其配体。 在小鼠中归巢和植入，我们将开发临床相关的方法来阻止 在整个应用过程中，重点将放在不影响正常HSC的情况下。 总之，这些研究应该产生重要的新知识。 这将提高 Ph+ 白血病过继免疫疗法和自体 HSCT 的有效性，以及 增加疾病治愈的患者比例。 PHS 398/2590（修订版 11/07）第 2 页继续格式页 项目总监/首席研究员（最后、第一、中间）：Van Etten R.A./Klingemann H.K.