Name: Amirah Muwahid
Lab Phone: 612-626-4217
Mail: 420 Delaware Street SE
Minneapolis, MN 55455
Dr. Miller has been interested in NK cell biology, NK cell development, the acquisition of NK cell receptors and seamless translation into clinical trials throughout his entire academic career. Currently, the lab is focused on mechanisms which determine the enhanced function seen with CMV induced adaptive NK cells, facilitating immune synapses with IL-15 containing Trispecific Killer Engagers (TriKEs), IL-15 biology, NK cell killer immunoglobulin receptor (KIR) acquisition and function (NK cell education), and developing NK cell therapeutics. Throughout his career at the University of Minnesota, he has mentored faculty and delivered hundreds of NK cells products to patients with cancer. His team has identified unique NKC2C+ NK cell repertoires exhibit a methylation signature of CD8+ T cells with properties of immune memory. Adaptive NK cells are distinctly different from canonical NK cells and signal through CD16 using a dominant CD3? signal by downregulation of FcR?R1?. Adaptive NK cells are better primed for killing, cytokine production, ADCC and exhibit unique metabolic signatures that enhance their survival. He has developed state-of-the-art functional readouts to study NK cells from the laboratory and the clinic based on high resolution testing. He was the first to report that haploidentical allogeneic human NK cells can persist and expand for up to one month after adoptive transfer. Based on these studies a significant part of his effort is trying to understand how to exploit NK cells for therapeutic purposes against infection and cancer and how to improve outcomes from allogeneic hematopoietic cell transplantation. Clinically, he has developed first-in-human trials using allogeneic donor NK cells, rhIL-15, IL-15/IL-15R?-Fc (ALT-803, now called N-803), an NK cell TriKE that engages NK cells and AML targets that costimulates NK cells with an IL-15 linker. Dr. Miller's experience and translational expertise has supported a transition from individual related donor NK cell products to induced pluripotent stem cell (iPSC) derived NK cells. Advantages of using this off-the-shelf platform include the flexibility of multiple gene edits, immediate cryopreserved product availability, multi-doing strategies and combinatorial therapy with targeted agents to enhance NK cell function. Dr. Miller is devoted to team science and mentoring. He has supervised > 400 NK cell products and sponsored >10 INDs and his team has studied >4000 transplant patients. Dr. Miller's experience, NIH grants and translational expertise provides a rich environment for training.
Natural Killer (NK) Cell Development
Throughout his academic career Dr. Miller has been interested in NK cell biology. His laboratory is focused on understanding the mechanisms of NK cell development and determining how NK cell killer immunoglobulin receptor (KIR) acquisition affects NK cell function through a process referred to as NK cell education or licensing. Most recently, he has been exploring the role of cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation in enhancing NK cell reconstitution and function. CMV is the only virus known to induce the development of ”adaptive” NK cells with memory properties which are long lived and exhibit enhanced responses to subsequent exposures. Dr. Miller and his team have identified these adaptive NK cells in humans and determined that they have a methylation signature remarkably similar to that of CD8+ T cells. His long-term goal is to translate these novel findings into better NK-cell based immunotherapies to treat cancer without the morbidity of CMV infection.
Targeted Immunotherapy to Treat Human Cancer
Dr. Miller was the first to report that related donor haploidentical allogeneic NK cells can expand after adoptive transfer and induce remission in patients with refractory leukemia. Building on this landmark study, he spends significant effort developing novel methods to exploit NK cells therapeutically to treat infections, to cure cancer and to improve outcomes from allogeneic hematopoietic cell transplantation (HCT). He also leads a focused effort to understand the association of KIR immunogenetics with protection against relapse after allogeneic HCT. Dr. Miller and his team have demonstrated that transplants from donors with favorable KIR genes protect against relapse of acute myeloid leukemia after unrelated donor HCT. He is currently testing novel strategies to activate NK cells in vivo (using novel proteins such as interleukin-15) and to create antigen-specific NK cells with Bispecific Killer Engagers (BiKEs), which are proteins that facilitate targeting of tumor antigens by NK cells.
Current Discovery & Research Themes in the Miller Laboratory:
- NK cells and their receptors after hematopoietic cell transplantation
- CMV induced adaptive NK cells exhibit enhanced function through CD16
- Induction of NK cells antigen specificity through CD16 targeting
- Preserving and enhancing NK cell function through antibody dependent cellular cytotoxicy (ADCC)
Bone marrow transplant; Cancer immunotherapy