Adoptive Cellular Therapy for Myeloid Leukemia

髓系白血病的过继细胞疗法

• 批准号: 7468677
• 负责人: JEFFREY J MOLLDREM
• 金额: $ 20.18万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468677
• 关键词: Adoptive Cell Transfers; Affinity; Agonist; Allogenic; Antigen Targeting; Antigens; Autologous; Bone Marrow Cells; CD8B1 gene; Cells; Clinical; Combined Modality Therapy; Complication; Cross Presentation; Cytotoxic T-Lymphocytes; Data; Disease; Disease remission; Drug Combinations; Effectiveness; Endopeptidases; Goals; Grant; Hematopoietic; Immune; Immune response; Immunity; Immunocompromised Host; Immunotherapy; Interferons; Leukocyte Elastase; Life; Long-Term Effects; Lymphocyte; Mediating; Memory; Methods; Molecular; Myeloid Leukemia; Names; Numbers; Patients; Peptide Hydrolases; Peptides; Phase; Phenotype; Process; Proteinase 3; Proteins; Rate; Refractory Disease; Relapse; Risk; Specificity; Stem cell transplant; Stem cells; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Toll-like receptors; Toxic effect; Transplant Recipients; Treatment Effectiveness; Vaccination; Vaccine Clinical Trial; Vaccines; Work; base; design; graft vs host disease; immunogenic; improved; in vivo; intracellular protein transport; killings; leukemia; pre-clinical; progenitor; protein localization location; response; reverse tolerance; success; trafficking

There is increasing evidence that lymphocytes can target and inhibit myeloid leukemia cells both in the allogeneic and autologous settings. The potent graft versus leukemia (GVL) effect associated with allogeneic stem cell transplant (SCT) conveys activity against leukemia and contributes to the decreased relapse risk compared with patients who do not receive an allogeneic graft. While GVL can induce long-term remission, the potentially lethal complication of graft-versus-host disease (GVHD) limits overall effectiveness of this treatment approach. We hypothesize that GVL would be enhanced, and GVHD reduced or eliminated, if the target antigens that drove those responses were identified, and if T cells with GVL antigen specificity could be isolated and adoptively transferred to patients with leukemia in the allogeneic setting, and that this effect could be increased by vaccination with appropriate leukemia antigens. We have identified an HLA-A2-restricted nonomer peptide, PR1, as a target antigen of CTL that inhibits myeloid leukemia progenitors and kills myeloid leukemia bone marrow cells. We have found that PR1 is processed from both proteinase 3 (PRTN3) and neutrophil elastase (ELA2), which are aberrantly expressed in leukemia. After vaccination with PR1, immune responses were observed in the majority of patients, and persistent remission was documented in some patients with AML, CML, and MDS. Immune-based therapies with low toxicity could be useful in combined treatment strategies to induce remission in patients with leukemia in the allogeneic setting to enhance GVL and minimize GVHD. In this proposal, we will (1) determine whether phenotype, function, and T cell receptor (TCR) affinity differ between PR1-CTL elicited after vaccination compared to those derived from healthy donors; (2) determine whether aberrant trafficking of PRTN3 and ELA2 can reverse tolerance and facilitate the expansion of central memory PR1-CTL; and (3) determine whether PR1-CTL expressing high affinity TCR can be transferred to patients with AML after T cell-depleted haplo-identical SCT to boost GVL and diminish GVHD. Lay Description: Stem cell transplantation has been used to successfully treat patients with leukemia, but the complication of graft-versus-host disease and the limited availability of suitable stem cell donors limit our use of this otherwise life-saving treatment to less than 25% of the potential patients who could benefit. To improve the effectiveness of SCT, we have identified some of the leukemia-associated target molecules recognized by the donor lymphocytes that mediate an immune effect against the patient's leukemia. We used one of these antigens, PR1, as a vaccine to boost immunity against leukemia in some patients with refractory disease. We found that PR1 vaccination was associated with little toxicity, and it boosted immunity in the majority of patients and induced remission in some patients, which has lasted up to seven years. In this proposal, we will study the molecular basis for immunity to this target, and we will use a strategy identified during the previous grant period to expand donor lymphocytes against this antigen, that we then transfer to patients with leukemia. If successful, this technique could eventually be used to reduce GVHD while retaining the beneficial effect of long-term remission after SCT.

越来越多的证据表明淋巴细胞可以靶向和抑制髓样白血病细胞，这两者都在同种异体中 和自动设置。与同种异体干细胞相关的有效移植物与白血病（GVL）效应 移植（SCT）传达了针对白血病的活性，并导致复发风险降低 未接受同种异体移植的患者。 GVL可以诱导长期缓解，但可能致命 移植物抗宿主病（GVHD）的并发症限制了这种治疗方法的总体有效性。我们 假设将增强GVL，并且如果靶抗原驱动这些抗原 鉴定了响应，如果可以分离具有GVL抗原特异性的T细胞并将转移到 在同种异体环境中患有白血病的患者，并且可以通过疫苗接种来增加这种作用 适当的白血病抗原。我们已经将HLA-A2限制的nonomer肽PR1确定为靶抗原 CTL抑制髓样白血病祖细胞并杀死髓样白血病骨髓细胞。我们发现 PR1是从蛋白酶3（PRTN3）和中性粒细胞弹性酶（ELA2）中处理的，它们均异常表达 在白血病。用PR1疫苗接种后，大多数患者观察到免疫反应，并且 一些AML，CML和MDS患者记录了持续缓解。基于免疫的疗法 低毒性对于联合治疗策略可能有用，以诱导白血病患者的缓解 同种异体设置以增强GVL并最小化GVHD。在此提案中，我们将（1）确定表型是否，是否 与那些相比 来自健康的捐助者； （2）确定PRTN3和ELA2的异常贩运是否可以逆转公差 并促进中央记忆PR1-CTL的扩展； （3）确定PR1-CTL是否表达高 在耗尽细胞的单倍型SCT后，可以将亲和力TCR转移给AML患者，以增强GVL和 减少GVHD。 外表描述：干细胞移植已用于成功治疗白血病患者，但 移植物抗宿主病的并发症和合适的干细胞供体的有限可用性限制了我们的使用 这种挽救生命的治疗方法不到25％的潜在患者可以受益。改善 SCT的有效性，我们已经确定了一些白血病相关的靶标分子 介导患者白血病的免疫作用的供体淋巴细胞。我们使用了其中之一 抗原，PR1作为一种疫苗，以增强某些难治性疾病患者的对白血病的免疫力。我们 发现PR1疫苗接种几乎没有毒性，并且它增强了大多数患者的免疫力 并诱发了一些患者的缓解，持续了长达七年。在此提案中，我们将研究 对该目标的免疫力的分子基础，我们将使用在上一个赠款期间确定的策略 扩展供体淋巴细胞针对这种抗原，然后我们转移到白血病患者。如果成功，这 最终可以使用技术来减少GVHD，同时保留长期缓解的有益效果 SCT之后。