Off-the-shelf engineered NK cells for the treatment of AML

用于治疗 AML 的现成工程 NK 细胞

• 批准号: 10058761
• 负责人: Katy Rezvani
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-20 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058761
• 关键词: Acute Myelocytic Leukemia; Allogenic; Allografting; Antigen-Presenting Cells; Biological; Bone Marrow Cell Transplantation; CASP9 gene; CD28 gene; Cancer Patient; Cell Culture Techniques; Cell Therapy; Cell physiology; Cells; Clinical; Clinical Trials; Data; Defect; Disease Progression; Dominant-Negative Mutation; Dose; Genes; Goals; Hematopoietic; Hematopoietic Stem Cell Transplantation; Homing; Human; IL3RA gene; Immune; Immunocompetent; Immunotherapy; Impairment; Infusion procedures; Innate Immune System; Interleukin-15; Interleukin-3 Receptor; K-562; Laboratories; Lymphocyte; Malignant Neoplasms; Measures; Mediating; Membrane; Methods; Myeloid Leukemia; Natural Killer Cell toxicity; Natural Killer Cells; Pathway interactions; Patient observation; Patient-Focused Outcomes; Patients; Phenotype; Play; Positioning Attribute; Pre-Clinical Model; Procedures; Protocols documentation; Recovery; Recovery of Function; Recurrent disease; Regulation; Relapse; Reproducibility; Research; Resistance; Retroviral Vector; Risk; Role; Safety; Siblings; Signal Transduction; Specificity; Surface; Surface Antigens; TGFBR2 gene; Testing; Toxic effect; Transforming Growth Factor beta; Translating; Transplantation; Treatment Failure; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; acute myeloid leukemia cell; antileukemic activity; base; cellular targeting; cellular transduction; chimeric antigen receptor; cost effective; cytokine; cytotoxic; cytotoxicity; disorder risk; effective therapy; engineered NK cell; ethnic minority population; graft vs leukemia effect; high risk; immune reconstitution; immunoregulation; immunotherapy clinical trials; improved; improved outcome; interleukin-21; leukemia; novel; novel strategies; peripheral blood; post-transplant; prevent; racial minority; reconstitution; relapse risk; stem cells; suicide gene; tumor-immune system interactions

Summary: Allogeneic hematopoietic transplantation (HSCT) is an effective treatment for AML. Relapse of the malignancy remains the major cause of treatment failure and improved strategies to eradicate leukemia are required. Natural killer (NK) cells are a unique class of lymphocytes, with cytotoxic, and immunoregulatory function which can mediate potent antileukemia effects against myeloid leukemias while simultaneously preventing GVHD in preclinical models. Relatively few NK cells are present in peripheral blood or bone marrow transplant cell products and the NK cells recovering early post transplant have functional defects impairing cytotoxicity. We have developed robust clinical procedures for the ex vivo expansion and activation of cord blood (CB)-derived NK cells. The long-tem objective of this research is to develop novel cell based therapies to harness the antileukemic potential of NK cells against AML, and to further enhance their effector function by both redefining their specificity and/or enhancing their potency Aim 1 tests the hypothesis that the addition of optimally selected, ex vivo expanded and activated CB-derived NK cells will improve the outcomes of patients with AML after cord blood transplantation (CBT). We have found that patients with AML whose HLA type is homozygous for group C2 have a significantly higher risk of relapse following CBT compared to those who are homozygous or heterozygous for HLA group C1. Mechanistically, we have shown that the increased risk of disease progression in the C2/C2 risk group is related to delayed emergence of immunocompetent C2-specific KIR2DL1/S1+ NK cells post-CBT. This suggests that such patients would benefit from the post-CBT infusion of activated mature CB-NK cells that express KIR2DL1/S1. Extensive biologic correlates will examine the phenotype, function and homing of adoptively infused CB-NK cells, and their impact on immune reconstitution post-transplant. Aim 2 capitalizes on the finding that the baseline cytotoxicity of NK cells can be augmented by expression of a chimeric antigen receptor (CAR) against the target cells. CD123, the α chain of the interleukin-3 receptor, is an attractive target for cellular immune therapy in AML, but cytotoxicity against normal hematopoietic cells would preclude safe delivery in the absence of HSCT. We will test the hypothesis that NK cells transduced with a CAR to CD123, and coexpressing CD28 and IL15 to mediate long term persistence, and inducible caspase 9 (IC9) to manage potential toxicity will provide enhanced activity against AML. Aim 3 examines if blocking the TGF-beta pathway by retrovirally transducing NK cells with a dominant negative TGF-beta type II receptor can render NK cells resistant to the immunosuppressive AML microenvironment. Optimal strategies formulated in aims 2 and 3 will be translated into human clinical trials, based on the optimal platform protocol determined in aim 1.

摘要： 异基因造血移植(HSCT)是治疗AML的有效方法。旧病复发 恶性肿瘤仍然是治疗失败的主要原因，并改进了根除白血病的策略 都是必需的。自然杀伤(NK)细胞是一类独特的淋巴细胞，具有细胞毒性和 免疫调节功能介导对髓系白血病的强大抗白血病作用 同时在临床前模型中预防移植物抗宿主病。相对较少的NK细胞存在于 外周血或骨髓移植细胞产物与NK细胞术后早期恢复 移植存在损害细胞毒性的功能缺陷。我们已经开发出强大的临床程序 用于脐带血(CB)来源的NK细胞的体外扩增和激活。的长期目标 这项研究旨在开发基于细胞的新疗法，以利用NK细胞的抗白血病潜力。 抗急性髓系白血病，并通过重新定义其特异性和/或 增强它们的效力目标1检验了这样一个假设，即添加最优选择的体外 扩增和激活脐带血来源的NK细胞将改善急性髓系白血病患者脐带术后的预后 血液移植(CBT)。我们发现，HLA型为纯合子的AML患者 C2组CBT术后复发风险显著高于 HLAC1型为纯合子或杂合子。从机制上讲，我们已经证明了增加的风险 C2/C2风险组的疾病进展与免疫活性延迟出现有关 CBT后C2特异性KIR2DL1/S1+NK细胞。这表明，这些患者将受益于 CBT后输注表达KIR2DL1/S1的激活的成熟CB-NK细胞。广泛的生物学 相关人员将检查过继输注的CB-NK细胞的表型、功能和归巢情况，以及他们的 对移植后免疫重建的影响。目标2利用了一个发现，即基线 抗NK细胞嵌合抗原受体(CAR)的表达可增强NK细胞的杀伤活性 目标单元格。CD123，白介素3受体的α链，是一个有吸引力的细胞靶点 急性髓系白血病的免疫治疗，但对正常造血细胞的细胞毒性将阻止安全交付 在没有HSCT的情况下。我们将验证NK细胞通过CAR转导到CD123的假设，并且 共表达CD28和IL15以介导长期持久性，并诱导caspase9(IC9) 管理潜在的毒性将增强对抗急性髓系白血病的活性。目标3检查是否阻止 逆转录病毒转导转化生长因子-βII型显性阴性NK细胞的转化生长因子-β途径 受体可使NK细胞对免疫抑制的急性髓系白血病微环境产生抵抗。最优 在目标2和目标3中制定的策略将转化为人体临床试验，基于最优 目标1中确定的平台协议。