Adoptive T-Cell Therapy for Acute Leukemia

急性白血病过继性 T 细胞疗法

• 批准号: 7791258
• 负责人: EDWARD David BALL
• 金额: $ 32.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791258
• 关键词: Acute; Acute Myelocytic Leukemia; Acute leukemia; Adoptive Immunotherapy; Allogenic; Antigen Presentation; Antigens; Autologous; Autologous Stem Cell Transplantation; B-Lymphocytes; Blast Cell; Blood; Blood Cells; CD8B1 gene; Cell Count; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell Separation; Cell Therapy; Cell surface; Cells; Chronic Myeloid Leukemia; Clinical; Clinical Trials; Cloning; Complex; Consolidation Therapy; Control Groups; Cytolysis; Cytotoxic T-Lymphocytes; Databases; Dendritic Cells; Diagnosis; Disease; Disease remission; Donor Lymphocyte Infusion; Dose; Dose-Limiting; Dose-Rate; Elements; Ensure; Generations; Growth Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; High Dose Chemotherapy; Immune response; Immune system; Immunosuppression; Immunotherapy; Infusion procedures; Interleukin-2; Laboratories; Lymphocyte; Lymphoid Cell; Maximum Tolerated Dose; Measures; Mediating; Methods; Microarray Analysis; Mononuclear; Multi-Institutional Clinical Trial; Myeloid Leukemia; Newly Diagnosed; Patients; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Population; Progression-Free Survivals; Proteins; Protocols documentation; Relapse; Research; Residual state; Safety; Site; Solid Neoplasm; Specificity; Stem cell transplant; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Protocols; Tumor Cell Line; autologous lymphocytes; cancer cell; chemotherapy; cohort; cytotoxic; design; graft vs host disease; innovation; killings; leukemia; neoplastic cell; novel; peripheral blood; phase 1 study; public health relevance; response; safety testing

DESCRIPTION (provided by applicant): There is evidence from allogeneic hematopoietic stem cell transplantation [HSCT] that there is an immune response against leukemia-associated antigens in patients with either acute or chronic myeloid leukemia (AML, CML). However, an autologous anti-tumor cell response in AML is either not evident or actively suppressed due to replacement of the lymphohematopoietic space with rapidly growing malignant cells. We have shown that specific AML-reactive T cells can be generated and expanded from primary cultures of mononuclear cells from all newly diagnosed patients with AML using a novel cell culture method employing sequential modulation of growth factors. This culture induces potent antigen presentation by inducing dendritic cell differentiation in the presence of autologous lymphocytes. The sensitized lymphocytes are then expanded through the use of growth factors. Large numbers (109-1010) of CD8+ T cells that are myeloid leukemia-specific are generated in this manner. In this novel study, we will employ the novel culture method to conduct a multi-center Phase 1/2 clinical trial of adoptive autologous T cell therapy in patients who have recently received an autologous HSCT (AHSCT) for AML. Peripheral blood cells will be obtained from patients with AML at first diagnosis or relapse, who are deemed eligible for AHSCT. Mononuclear cells containing AML blasts and normal T cells will be cryopreserved. The patient will then be treated and at the time high dose therapy for AHSCT is administered the cell culture will be initiated in a central lab. The cultured T cells will then be tested for their ability to kill autologous AML cells and to ensure the absence of residual AML. The T cells will be infused into the patient approximately 5 weeks after AHSCT. Cohorts of patients will be observed for safety after infusion of graded numbers of T cells (primary endpoint) and all patients will be observed for 1 year to determine progression-free survival, compared with our large institutional database. This innovative protocol will determine whether cellular immunotherapy with autologous cytotoxic T cells is safe and has the potential for therapeutic benefit in patients with AML. PUBLIC HEALTH RELEVANCE: This proposal involves a novel multi-center clinical trial testing the safety and efficacy of infusing autologous cytotoxic T cells in patients with acute myeloid leukemia who have recently undergone autologous stem cell transplantation. The autologous T cells will be generated through induction of dendritic cell differentiation of AML cells in cell cultures obtained at the time of diagnosis. We hypothesize that these autologous T cell infusions will be safe and effective at decreasing relapse rates following autologous stem cell transplantation.

描述（由申请人提供）：有来自异基因造血干细胞移植[HSCT]的证据表明，急性或慢性髓性白血病（AML，CML）患者中存在针对白血病相关抗原的免疫应答。然而，AML中的自体抗肿瘤细胞应答要么不明显，要么由于淋巴造血空间被快速生长的恶性细胞替代而受到积极抑制。我们已经证明，使用一种新的细胞培养方法，采用生长因子的顺序调节，可以从所有新诊断的AML患者的单核细胞的原代培养物中产生和扩增特异性AML反应性T细胞。该培养物通过在自体淋巴细胞存在的情况下诱导树突状细胞分化来诱导有效的抗原提呈。然后通过使用生长因子扩增致敏的淋巴细胞。以这种方式产生大量（109-1010）骨髓性白血病特异性的CD 8 + T细胞。在这项新的研究中，我们将采用新的培养方法在最近接受自体HSCT（AHSCT）治疗AML的患者中进行过继自体T细胞治疗的多中心1/2期临床试验。外周血细胞将从首次诊断或复发的AML患者中获得，这些患者被认为有资格接受AHSCT。将含有AML原始细胞和正常T细胞的单核细胞冷冻保存。然后将对患者进行治疗，在给予AHSCT高剂量治疗时，将在中心实验室开始细胞培养。然后将测试培养的T细胞杀死自体AML细胞的能力，并确保不存在残留的AML。AHSCT后约5周，将T细胞输注至患者体内。将在输注分级数量的T细胞（主要终点）后观察患者队列的安全性，并将所有患者观察1年，以确定与我们的大型机构数据库相比的无进展生存期。这项创新方案将确定自体细胞毒性T细胞的细胞免疫疗法是否安全，并有可能在AML患者中获得治疗益处。 公共卫生相关性：该提案涉及一项新的多中心临床试验，测试在最近接受自体干细胞移植的急性髓性白血病患者中输注自体细胞毒性T细胞的安全性和有效性。通过在诊断时获得的细胞培养物中诱导AML细胞的树突状细胞分化来产生自体T细胞。我们假设这些自体T细胞输注在降低自体干细胞移植后的复发率方面是安全有效的。