Adoptive T-Cell Therapy for Acute Leukemia

描述(申请人提供)：异基因造血干细胞移植[HSCT]的证据表明，在急性或慢性髓系白血病(AML，CML)患者中存在针对白血病相关抗原的免疫反应。然而，由于淋巴造血区被快速生长的恶性细胞取代，AML的自体抗肿瘤细胞反应要么不明显，要么受到积极抑制。我们已经证明，使用一种新的细胞培养方法，利用顺序调节生长因子的方法，可以从所有新诊断的AML患者的单个核细胞的原代培养中产生和扩增特定的AML反应性T细胞。这种培养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来扩增致敏的淋巴细胞。大量(109-1010)髓系白血病特异的CD8+T细胞是以这种方式产生的。在这项新的研究中，我们将使用新的培养方法对最近接受AML自体造血干细胞移植(AHSCT)的患者进行过继自体T细胞治疗的多中心1/2期临床试验。外周血细胞将从初诊或复发的AML患者身上获得，这些患者被认为有资格接受AHSCT。含有AML原始细胞和正常T细胞的单个核细胞将被冷冻保存。然后患者将接受治疗，在进行大剂量AHSCT治疗时，细胞培养将在中心实验室启动。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。T细胞将在AHSCT后大约5周被注入患者体内。与我们的大型机构数据库相比，在输注分级数量的T细胞(主要终点)后，将观察患者队列的安全性，并将观察所有患者一年，以确定无进展生存率。这一创新的方案将确定使用自体细胞毒性T细胞进行细胞免疫治疗是否安全，并具有治疗急性髓细胞白血病患者的潜力。 公共卫生相关性：这项建议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系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。在诊断时获得的细胞培养中，通过诱导AML细胞的树突状细胞分化，将产生自体T细胞。我们推测，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和有效的。

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.