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

• 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
• 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

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.

项目概要 自然杀伤 (NK) 细胞是有效的效应淋巴细胞，能够杀死恶性细胞和病毒感染细胞 通过释放裂解颗粒来攻击细胞，无需抗原特异性。急性髓系白血病 (AML) 和 多发性骨髓瘤 (MM) 对 NK 细胞介导的杀伤高度敏感。使用供体 NK 细胞的策略 治疗这些恶性肿瘤已经在超过三分之一的患者中产生了临床反应，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 细胞 治疗受到输注细胞寿命短和功能衰竭发生的限制。 当 NK 细胞暴露于肿瘤微环境时就会发生这种情况。 NK 细胞的一个子集，称为“适应性” 因巨细胞病毒 (CMV) 感染而发生。适应性 NK 细胞比传统 NK 细胞寿命更长 细胞具有强大的分泌细胞因子的能力，并且对肿瘤的抑制具有抵抗力 微环境。我们证明，移植后适应性 NK 细胞扩增与 26% AML 复发率降低，MM 复发率降低 53%。我们的实验室开发了一种可靠的方法 从 CMV 血清阳性供体的外周血中扩增适应性 NK 细胞；然而，我们的初步数据 还表明，通过激活受体 NKG2C 联合慢性刺激适应性 NK 细胞 与炎症细胞因子结合，诱导检查点抑制受体的高表达。我们力求 描述用于治疗 AML 或 MM 的适应性 NK 细胞的体内行为。在目标 1 中，我们将 确定适应性 NK 细胞是否比传统 NK 细胞存活时间更长并运输至骨髓 同种异体输注后。患者样本将从正在进行的 I/II 期临床试验中收集，使用 同种异体、适应性 NK 细胞用于治疗复发性 AML。此外，我们将测试适应性 NK 细胞的持久性和 在 MM 小鼠模型中，与传统 NK 细胞疗法相比，其寿命更长。在目标 2 中，我们将确定 NK 细胞耗竭机制并测试检查点受体阻断是否可以恢复 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·米勒博士的指导。 Merino 博士目前是博士后研究员，但将成为一名讲师 完成她的进修培训后。 Miller 博士是 NK 细胞治疗领域的领导者，拥有以下记录： 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 癌症中心为培养转化癌症研究的职业生涯提供了优越的环境。到 为了实现成为独立研究者的长期目标，Merino 博士招募了一名顾问 顶尖科学家委员会并制定了旨在扩大她的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。