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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：
10365991
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/10365991
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 Therapy Cell physiology Cells Cellular biology Chronic Clinical Clinical Trials Cytomegalovirus Cytomegalovirus Infections Cytoplasmic Granules Data 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 Lead Leadership Longevity Lymphocyte Lytic Malignant - descriptor Malignant Neoplasms Mediating Mentorship Methods Minnesota Multiple Myeloma Mus NK cell therapy Natural Increases Natural Killer Cells Patients Phase I/II Clinical Trial Phase I/II Trial Postdoctoral Fellow Records Refractory Relapse Reporting Research Research Personnel Resistance Safety Sampling Scientist Specificity Stem cell transplant Technical Expertise Testing Time Training Transfusion Translating Transplantation Universities Viral Work base 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 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.

项目总结