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: 8091371
• 负责人: Michael C Jensen
• 金额: $ 54.33万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091371
• 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 Therapy; 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 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; public health relevance; 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. PUBLIC HEALTH RELEVANCE: The majority of adults and a significant fraction of children that develop acute lymphoblastic leukemia (ALL) will die of progressive disease. The studies in this application will evaluate adoptive T cell therapy for ALL as an adjunct to hematopoietic stem cell transplantation using T cells that have an innate capacity to persist in vivo and are engineered to recognize a molecule expressed on the earliest leukemia progenitors. If this therapy safely eliminates residual ALL, this will improve the outcome of hematopoietic stem cell transplantation and provide opportunities to reduce the intensity of the preparative regimen and employ this therapy in the non-transplant setting.

描述（由申请人提供）：急性淋巴细胞白血病（所有）约占成人所有急性白血病的20％，并且是儿童期诊断出的最常见癌症。接受强化化疗的儿童的治疗率显着提高，但成年人的预后仍然很差。同种异体造血干细胞移植（HCT）是对所有具有适当捐赠者的儿童的选择治疗方法，并且越来越多地用于治疗成年人。供体选择和支持性护理的进步改善了所有经历同种异体HCT的患者的结果，白血病复发或与移植物抗抗宿主病（GVHD）有关的并发症已成为治疗失败的最常见原因。原则上，通过过继的T细胞疗法靶向恶性细胞可以提供一种治疗方法，对正常细胞的毒性可以忽略不计。该项目旨在促进HCT后白血病细胞的免疫学清除，而不会通过对表达所有茎和祖细胞上CD19分子特异的嵌合抗原受体（CAR）进行工程的T细胞的过继转移而加剧GVHD。共同研究者在非人类灵长类动物模型中的最新协作工作表明，源自中心记忆（TCM）细胞子集的病毒特异性T细胞具有长期在体内持续存在的能力并建立功能性T细胞存储器的储层。在初步工作中，我们开发了与CD19-特异性CAR相关的人类中央记忆T细胞（CMV）PP65所必需的试剂。在该项目中，我们将优化用于临床应用的细胞加工方法，并进行临床试验，在HCT之后，将对“双特异性” T细胞转移“双特异性” T细胞，以促进抗血清学效应。具体目的是：目标1。用供体TCM衍生的双特异性（CMVPP65XCD19）CD8+ TE克隆的CD19+患者的供体TCM衍生的双特异性（CMVPP65XCD19）的安全性和抗肿瘤活性，均与HLA匹配的同种异体HLCT匹配。 AIM 2。评估新型CD19特异性CAR矢量，该矢量编码标记，以快速选择转导的T细胞和与CD36链条串联的共刺激结构域。公共卫生相关性：大多数成年人和大部分患有急性淋巴细胞白血病（ALL）的儿童将死于进行性疾病。该应用中的研究将评估所有人对造血干细胞移植的辅助的产物T细胞疗法，使用具有先天能力持续体内的能力的T细胞，并经过精心设计以识别以最早的白血病祖细胞表达的分子。如果这种疗法安全地消除了全部残留，这将改善造血干细胞移植的结果，并为降低制剂疗法的强度提供机会，并在非移植群落环境中采用这种疗法。