Adoptive T-Cell Therapy for Acute Leukemia

描述（由申请人提供）：同种异体造血干细胞移植[HSCT]的证据表明，急性或慢性髓性白血病（AML， CML）患者存在针对白血病相关抗原的免疫应答。然而，由于淋巴造血空间被快速生长的恶性细胞所取代，AML的自体抗肿瘤细胞反应要么不明显，要么被积极抑制。我们已经证明，使用一种采用顺序调节生长因子的新型细胞培养方法，可以从所有新诊断的AML患者的单核细胞原代培养中产生和扩增特异性AML反应性T细胞。这种培养通过在自体淋巴细胞存在下诱导树突状细胞分化诱导强效抗原呈递。然后通过使用生长因子扩大致敏淋巴细胞。大量（109-1010）的CD8+ T细胞是髓性白血病特异性的，以这种方式产生。在这项新颖的研究中，我们将采用新的培养方法对最近接受过自体造血干细胞移植（AHSCT）治疗AML的患者进行过继性自体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患者中获取，这些患者被认为符合AHSCT的条件。含有AML原细胞和正常T细胞的单核细胞将被冷冻保存。然后对患者进行治疗，同时对AHSCT进行高剂量治疗，细胞培养将在中心实验室开始。然后将测试培养的T细胞杀死自体AML细胞的能力，并确保没有残留的AML。这些T细胞将在AHSCT后大约5周输注到患者体内。与我们的大型机构数据库相比，将对输注分级数量T细胞后的患者队列进行安全性观察（主要终点），所有患者将观察1年以确定无进展生存期。这一创新方案将确定使用自体细胞毒性T细胞的细胞免疫疗法是否安全，并具有治疗急性髓性白血病患者的潜在益处。

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.