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

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.