Targeted therapy of ALL with gene-modified central memory T cells

使用基因修饰的中央记忆 T 细胞靶向治疗 ALL

• 批准号: 8473662
• 负责人: Michael C Jensen
• 金额: $ 50.87万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8473662
• 关键词: Accounting; Acute Lymphocytic Leukemia; Acute leukemia; Adoptive Transfer; Adult; Allogenic; Antigen Receptors; Antigens; B-Cell Acute Lymphoblastic Leukemia; CD19 Antigens; CD19 gene; CD3 Antigens; CD36 gene; CD8B1 gene; Cell Survival; Cell physiology; Cell surface; Cells; Child; Childhood; Clinical; Clinical Trials; Cytomegalovirus; Disease remission; Donor Selection; Employee Strikes; Engineering; Engraftment; Epidermal Growth Factor Receptor; Gene-Modified; Genetic; Health; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immune system; Immunologics; In Vitro; Interleukin-15; Leukemic Cell; Link; Malignant Neoplasms; Mediating; Memory; Methodology; Methods; Modeling; Modification; Normal Cell; Outcome; Patients; Principal Investigator; Probability; Progressive Disease; Prophylactic treatment; Reagent; Regimen; Relapse; Residual state; SELL gene; Safety; Stem cell transplant; Stem cells; Subfamily lentivirinae; Supportive care; T cell therapy; T memory cell; T-Lymphocyte; Techniques; Time; Toxic effect; Transplantation; Treatment Efficacy; Treatment Failure; Virus; Work; arm; cancer cell; cancer diagnosis; cellular engineering; chemotherapy; clinical application; graft vs host disease; improved; in vivo; leukemia; migration; nonhuman primate; novel; outcome forecast; progenitor; response; stem; terminally differentiated effector memory (TEM) T cells; tumor; vector

DESCRIPTION (provided by applicant): Acute lymphoblastic leukemia (ALL) accounts for approximately 20% of all acute leukemia seen in adults, and is the single most common cancer diagnosed during childhood. Cure rates have improved significantly for children who receive intensive chemotherapy, but the prognosis for adults remains poor. Allogeneic hematopoietic stem cell transplantation (HCT) is the salvage treatment of choice for children with relapsed ALL who have appropriate donors and is increasingly being used to treat adults in first remission. Advances in donor selection and supportive care have improved the outcome for patients with ALL undergoing allogeneic HCT, and leukemia relapse or complications related to graft-versus-host disease (GVHD) have emerged as the most common causes of treatment failure. In principle, targeting malignant cells by adoptive T cell therapy could provide an approach to therapy that would have negligible toxicity to normal cells. This project seeks to promote the immunologic clearance of leukemic cells after HCT without aggravating GVHD by the adoptive transfer of T cells that are engineered to express a chimeric antigen receptor (CAR) specific for the CD19 molecule on ALL stem and progenitor cells. Recent collaborative work by the Co- Principal Investigators in a nonhuman primate model has demonstrated that virus-specific T cells derived from the central memory (TCM) subset of cells have the ability to persist long-term in vivo and establish a reservoir of functional T cell memory. In preliminary work, we have developed reagents necessary to arm human central memory T cells specific for cytomegalovirus (CMV) pp65 with a CD19- specific CAR. In this project, we will optimize the cell processing methods for clinical application and conduct a clinical trial in which "bi-specific" T-cells will be adoptively transferred following HCT to promote an antileukemic effect. The specific aims are: Aim 1. To determine the safety and anti-tumor activity of adoptive therapy with donor TCM-derived bi-specific (CMVpp65xCD19) CD8+ TE clones for patients with CD19+ ALL following HLA matched allogeneic HCT. Aim 2. To evaluate novel CD19-specific CAR vectors that encode a marker for rapid selection of transduced T cells and a costimulatory domain in tandem with the CD36 chain.

描述（由申请人提供）：急性淋巴细胞白血病 (ALL) 约占成人所有急性白血病的 20%，是儿童时期诊断出的最常见的癌症。接受强化化疗的儿童的治愈率显着提高，但成人的预后仍然较差。异基因造血干细胞移植 (HCT) 是有合适供体的复发性 ALL 儿童的首选挽救治疗方法，并且越来越多地用于治疗首次缓解的成人。供体选择和支持治疗方面的进步改善了接受同种异体 HCT 的 ALL 患者的预后，而白血病复发或与移植物抗宿主病 (GVHD) 相关的并发症已成为治疗失败的最常见原因。原则上，通过过继性 T 细胞疗法靶向恶性细胞可以提供一种对正常细胞毒性可忽略不计的治疗方法。该项目旨在通过 T 细胞的过继转移来促进 HCT 后白血病细胞的免疫清除，而不加重 GVHD，这些 T 细胞经过工程改造，可表达对 ALL 干细胞和祖细胞上的 CD19 分子具有特异性的嵌合抗原受体 (CAR)。联合首席研究员最近在非人类灵长类动物模型中的合作工作表明，源自中央记忆 (TCM) 细胞子集的病毒特异性 T 细胞能够在体内长期存在，并建立功能性 T 细胞库。细胞记忆。在前期工作中，我们开发了必要的试剂，用 CD19 特异性 CAR 武装巨细胞病毒 (CMV) pp65 特异性的人类中央记忆 T 细胞。在这个项目中，我们将优化临床应用的细胞处理方法，并进行临床试验，在HCT后过继转移“双特异性”T细胞以促进抗白血病效果。具体目标是： 目标 1. 确定 HLA 匹配同种异体 HCT 后使用供者中药来源的双特异性 (CMVpp65xCD19) CD8+ TE 克隆对 CD19+ ALL 患者进行过继治疗的安全性和抗肿瘤活性。目标 2. 评估新型 CD19 特异性 CAR 载体，该载体编码用于快速选择转导 T 细胞的标记以及与 CD36 链串联的共刺激结构域。