Understanding and improving responses to adaptive NK cell therapy for leukemia and multiple myeloma

了解和改善对白血病和多发性骨髓瘤的适应性 NK 细胞疗法的反应

基本信息

批准号：
10591592
负责人：
Aimee Merino
金额：
$ 14.87万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-05 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591592
关键词：
Acute Myelocytic Leukemia Acute leukemia Adaptive Behaviors Adoptive Transfer Advisory Committees Allogenic Antigens Antitumor Response Autologous Transplantation Blood Cells Blood specimen Bone Marrow Bone Marrow Transplantation Cancer Center Cell Density Cell Survival Cell Therapy Cell physiology Cells Cellular biology Chronic Clinical Clinical Trials Collecting Cell Cytomegalovirus Cytomegalovirus Infections Cytoplasmic Granules Data Engraftment Enrollment Environment Exhibits Exposure to Fellowship Follow-Up Studies Funding Future Goals Hematopoietic Neoplasms Human Immune Immunologic Memory In Vitro In complete remission Inflammatory Infusion procedures Leadership Longevity Lymphocyte Lytic Malignant - descriptor Malignant Neoplasms Mediating Mentorship Methods Minnesota Multiple Myeloma Mus NK cell therapy Natural Killer Cells Patients Phase I/II Clinical Trial Phase I/II Trial Postdoctoral Fellow Predisposition Records Refractory Relapse Reporting Research Research Personnel Resistance Safety Sampling Scientist Specificity Stem cell transplant Technical Expertise Testing Time Training Transfection Transfusion Translating Transplantation Universities Viral Work blood treatment cancer cell cancer therapy career cell killing checkpoint receptors clinical application cytokine efficacy testing exhaust exhaustion experience follow-up functional restoration immune checkpoint blockade improved in vitro Assay in vivo instructor knowledge base leukemia leukemia relapse leukemia treatment loss of function mouse model neoplastic cell novel novel strategies peripheral blood phenotypic biomarker primary outcome prospective receptor receptor expression recruit response seropositive skills success trafficking translational cancer research tumor microenvironment

项目摘要

Project Summary Natural killer (NK) cells are potent, effector lymphocytes with the ability to kill malignant and virally infected cells by releasing lytic granules without the need for antigen specificity. Acute myeloid leukemia (AML) and multiple myeloma (MM) are highly susceptible to NK cell-mediated killing. Strategies using donor NK cells to treat these malignancies have yielded clinical responses in more than a third of patients, even allowing some refractory AML patients to eventually get a curative bone marrow transplant. Despite these successes, NK cell therapy has been limited by the short life span of infused cells and the occurrence of functional exhaustion that occurs when NK cells are exposed to the tumor microenvironment. A subset of NK cells, termed ‘adaptive’ develops in response to cytomegalovirus (CMV) infection. Adaptive NK cells live longer than conventional NK cells, have a robust capacity to secrete cytokines, and are resistant to suppression in the tumor microenvironment. We demonstrated that adaptive NK cell expansion after transplant is associated with a 26% reduction in AML relapse and a 53% reduction in MM relapse. Our lab has developed a reliable method to expand adaptive NK cells from peripheral blood of CMV seropositive donors; however, our preliminary data also shows that chronic stimulation of adaptive NK cells through the activating receptor NKG2C, in combination with inflammatory cytokines, induces high expression of checkpoint inhibitory receptors. We seek to characterize the in vivo behavior of adaptive NK cells given as therapy for AML or MM. In Aim 1, we will determine whether adaptive NK cells survive longer than conventional NK cells and traffic to the bone marrow after allogeneic infusion. Patient samples will be collected from an ongoing phase I/II clinical trial using allogeneic, adaptive NK cells to treat relapsed AML. In addition, we will test adaptive NK cell persistence and longevity compared to conventional NK cell therapy in a murine model of MM. In Aim 2, we will identify mechanisms of NK cell exhaustion and test whether checkpoint receptor blockade restores NK cell function. These studies will be led by Dr. Aimee Merino, at the University of Minnesota Masonic Cancer Center, under the mentorship of Dr. Jeffrey Miller. Dr. Merino is currently a postdoctoral fellow, but will become an instructor upon completion of her fellowship training. Dr. Miller is a leader in NK cellular therapy with a track record of translating discoveries in NK cell biology into novel clinical applications. The University of Minnesota Masonic Cancer Center offers an exceptional environment for cultivating a career in translational cancer research. To achieve the long-term goal of becoming an independent investigator, Dr. Merino has recruited an advisory committee of leading scientists and developed a training plan aimed at broadening her knowledge base, developing her technical expertise, and cultivating her leadership skills.

项目摘要天然杀手（NK）细胞是潜在的，效应淋巴细胞具有杀死恶性并实际感染的能力通过释放裂解颗粒而无需抗原特异性。急性髓样白血病（AML）和多发性骨髓瘤（MM）非常容易受到NK细胞介导的杀伤的影响。使用供体NK细胞的策略治疗这些恶性肿瘤已在超过三分之一的患者中产生临床反应，甚至允许一些患者难治性AML患者最终获得治愈性骨髓移植。尽管取得了这些成功，NK单元治疗受感染细胞的寿命短，以及功能疲劳的发生限制当NK细胞暴露于肿瘤微环境时，就会发生。 NK细胞的子集，称为“自适应” 响应巨细胞病毒（CMV）感染的发展。自适应NK细胞的寿命比常规NK更长细胞，具有强大的秘密细胞因子的能力，并且对肿瘤的抑制具有抗性微环境。我们证明了移植后的自适应NK细胞扩展与26％有关减少AML缓解率和MM缓解率降低53％。我们的实验室已经开发了一种可靠的方法从CMV血清阳性供体的外周血中扩展自适应NK细胞；但是，我们的初步数据还表明，通过激活受体NKG2C的慢性刺激自适应NK细胞组合伴有炎症性细胞因子，诱导了检查点抑制受体的高表达。我们寻求表征自适应NK细胞作为AML或MM治疗的体内行为。在AIM 1中，我们将确定自适应NK细胞是否比常规NK细胞的生存时间更长，并传播到骨髓同种异体输注后。患者样品将从正在进行的I/II期临床试验中收集同种异体，适应性NK细胞以治疗继电器AML。此外，我们将测试自适应NK细胞的持久性和与传统的NK细胞疗法相比，在MM的鼠模型中，寿命。在AIM 2中，我们将确定 NK细胞耗尽的机制并测试检查点受体阻滞是否恢复NK细胞功能。这些研究将由明尼苏达大学共济会癌症中心的Aimee Merino博士领导杰弗里·米勒（Jeffrey Miller）博士的精神训练。 Merino博士目前是博士后研究员，但将成为一名教练完成研究金培训后。 Miller博士是NK蜂窝疗法的领导者将NK细胞生物学的发现转化为新的临床应用。明尼苏达大学共济会癌症中心为培养翻译癌症研究的职业提供了一个非凡的环境。到实现成为独立研究者的长期目标，Merino博士招募了咨询领先科学家委员会并制定了旨在扩大其知识基础的培训计划，发展她的技术专长，并培养她的领导能力。