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

用于治疗 AML 的现成工程 NK 细胞

基本信息

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
项目类别：
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

项目摘要

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：异基因造血移植（HSCT）是治疗 AML 复发的有效方法。恶性肿瘤仍然是治疗失败的主要原因，需要改进根除白血病的策略自然杀伤 (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，可介导针对髓性白血病的有效抗白血病作用同时在临床前模型中预防 GVHD 的 NK 细胞相对较少。外周血或骨髓移植细胞产品以及术后早期恢复的 NK 细胞移植有损害细胞毒性的功能缺陷。用于脐带血 (CB) 衍生的 NK 细胞的离体扩增和激活。这项研究旨在开发新型细胞疗法，以利用 NK 细胞的抗白血病潜力对抗 AML，并通过重新定义其特异性和/或进一步增强其效应功能增强其效力目标 1 检验以下假设：添加最佳选择的离体扩增和活化的 CB 衍生 NK 细胞将改善 AML 患者脐带血移植后的预后我们发现 AML 患者的 HLA 类型为纯合子。与 CBT 组相比，C2 组在 CBT 后复发的风险显着更高从机制上讲，我们已经证明 HLA C1 组的纯合子或杂合子风险增加。 C2/C2 风险组的疾病进展与免疫活性的延迟出现有关 CBT 后 C2 特异性 KIR2DL1/S1+ NK 细胞这表明此类患者将从 CBT 中受益。 CBT 后输注表达 KIR2DL1/S1 的活化成熟 CB-NK 细胞。相关人员将检查过继输注的 CB-NK 细胞的表型、功能和归巢及其归巢目标 2 利用了基线的发现。 NK细胞的细胞毒性可以通过表达嵌合抗原受体（CAR）来增强 CD123（白细胞介素 3 受体的 α 链）是细胞的一个有吸引力的靶点。 AML 的免疫治疗，但针对正常造血细胞的细胞毒性会妨碍安全分娩在没有 HSCT 的情况下，我们将测试 NK 细胞用 CAR 转导为 CD123 的假设，以及共表达 CD28 和 IL15 以介导长期持久性，诱导型 caspase 9 (IC9) 以介导长期持久性控制潜在的毒性将增强抗 AML 的活性，目标 3 检查是否阻断了 AML。通过逆转录病毒转导具有显性负性 TGF-β II 型的 NK 细胞来实现 TGF-β 途径受体可以使 NK 细胞对免疫抑制性 AML 微环境产生抵抗。目标 2 和 3 中制定的策略将根据最佳效果转化为人体临床试验目标 1 中确定的平台协议。