My basic science research program focuses on benign and malignant lymphocyte biology, which informs a translational immunotherapy effort to develop novel treatments for cancer patients.
Basic and Translational Natural killer (NK) Cell Biology
The long term goals of this research program are to better understand the cellular networks and molecular programs that regulate natural killer (NK) cell development and activation, and translate basic NK cell biology into novel treatments for patients with cancer.
The role of microRNAs in regulating NK cell development and function
MicroRNAs are a large family of non-coding RNAs that control the production of proteins. Our laboratory uses next-generation sequencing to identify the expressed microRNAs in human and mouse NK cells, including developmental and functional subsets, and NK cells arising in different tissue. We use mouse genetic models to investigate the mechanistic role of microRNAs in NK cell development and function. In addition, we have developed techniques to elucidate the regulatory role of microRNAs in human NK cells. Global knockout of microRNA biogenesis (dicer1) in mouse NK cells has revealed a marked impact on NK cell development and functionality. The study of how individual microRNAs expressed in NK cell impact NK cell biology is ongoing, and recent work has identified a role for miR-155 in setting the activation threshold of NK cells.
Utilizing cytokines to function enable NK cells
Cytokines are the communication system used by immune cells to signal the need to home to sites of infection or cancer, grow, survive, and become highly functional. Our laboratory studies how cytokines may activate human and mouse NK cells, with the translational goal of developing new immunotherapy approaches. One example is cytokine-induced memory-like NK cells, where our laboratory in collaboration with Dr. Megan Cooper, identified a novel way to enhance human NK cell activity against cancer cell targets. This involves a brief, combined pre-activation with IL-12, IL-15, and IL-18. Ongoing work evaluates the mechanisms whereby human CIML NK cells maintain enhanced functionality and establishes the framework for their use as cancer immunotherapy.
Clinical trials utilizing NK cells or drugs that enhance NK cell function
Lenalidomide in hematologic malignancies. Two phase 2 trials of the immunomodulatory drug lenalidomide have shown activity in acute myeloid leukemia and Hodgkin lymphoma, and our laboratory is investigating the impact of lenalidomide on NK cells in patients. A third clinical trial investigates the potential for using lenalidomide after a stem cell transplant for patient with relapsed Hodgkin lymphoma. These clinical studies have been performed in collaboration with Drs. Nancy Bartlett and Ravi Vij.
CIML NK cells for relapsed or refractory AML. This is a first in human phase 1 study of allogeneic CIML NK cells (pre-activated with IL-12, IL-15, and IL-18), an approach identified in our laboratory in human NK cell pre-clinical studies. The goal of this trial is to establish the safety of this adoptive immunotherapy and improve our understanding of human CIML NK cell biology in vivo. This study is being performed in collaboration with Dr. Rizwan Romee, who oversees the clinical trial.
Additional clinical trials involving NK cells include: selecting a favorable KIR donor in unrelated HSCT for AML with the goal of this study is to utilize killer cell immunoglobulin-like receptor (KIR) genes to choose the optimal unrelated donor for patients undergoing stem cell transplantation for AML; and using CNDO-109 activated allogeneic NK cells in a phase 1 / 2 clinical trial in which NK cells are administered to acute myeloid leukemia patients who have obtained a complete remission, but require additional treatment to prevent relapse.
Lymphoma Genomics and Biology
The long term goals of this research program are to advance our understanding of how lymphoma develops and progresses, and use this knowledge to develop new prognostic and therapeutic approaches for lymphoma patients.
Clinical and pathogenic impact of genomic variants in follicular NHL
Discovery and targeted next-generation DNA sequencing of follicular lymphoma will be used to define the recurrence of somatic genomic alterations and their impact on clinical outcomes. This project is performed in collaboration with The Genome Institute at Washington University.
Additional information about our research and team: www.fehnigerlab.org