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.

概括： 同种异体造血移植（HSCT）是AML的有效治疗方法。复发 恶性肿瘤仍然是治疗失败的主要原因和改进的放射性白血病的策略 需要。天然杀手（NK）细胞是一类独特的淋巴细胞，具有细胞毒性，并且 免疫调节功能可以介导对髓样白血病的有效抗肺血症作用 同时在临床前模型中预防GVHD。 NK细胞相对较少 周围血液或骨髓移植细胞产物和NK细胞提早恢复 移植具有功能缺陷，会损害细胞毒性。我们已经开发了强大的临床程序 用于离体膨胀和脐带血（CB）衍生的NK细胞的激活。长节的目标 这项研究是开发基于新型细胞的疗法来利用NK细胞的抗毒素潜力 反对AML，并通过重新定义其特异性和/或进一步增强其效应子功能 增强他们的效力目标1检验了以下假设：添加最佳的外体内 扩展和激活的CB衍生的NK细胞将改善脐带后AML患者的结局 血液移植（CBT）。我们发现，HLA类型的AML患者是纯合的 C2组在CBT之后的继电器风险明显更高 HLA组C1的纯合或杂合。从机械上讲，我们已经证明了风险增加 C2/C2风险组的疾病进展与免疫能力的延迟出现有关 C2特异性KIR2DL1/S1+ NK细胞CBT。这表明此类患者将从 CBT在表达KIR2DL1/S1的活化成熟的CB-NK细胞中输注。广泛的生物学 相关性将检查适当注入CB-NK细胞的表型，功能和归巢及其 对移植后免疫结构的影响。 AIM 2利用了基线的发现 通过表达嵌合抗原受体（CAR），可以增强NK细胞的细胞毒性 目标细胞。 CD123是白介素-3受体的α链，是细胞的有吸引力的靶标 AML的免疫治疗，但针对正常造血细胞的细胞毒性将排除安全递送 在没有HSCT的情况下。我们将检验以下假设，即NK细胞用汽车转移至CD123，并且 共表达CD28和IL15以介导长期持久性，并诱导的caspase 9（IC9）至 管理潜在的毒性将提供对AML的活动增强。 AIM 3考试如果阻止 TGF-β途径通过逆转录病毒转导的NK细胞具有显性负TGF-beta II型 受体可以使NK细胞具有抗性免疫抑制AML微环境。最佳的 AIM 2和3中制定的策略将基于最佳方式转化为人类临床试验 在AIM 1中确定的平台协议。