Research in the laboratory of Todd Fehniger, MD, PhD, focuses on Natural Killer (NK) cell biology and therapeutics, immunotherapy, and lymphoma genomics. NK cells are innate lymphoid cells that mediate anti-tumor immune responses and are important for defense against pathogens. Lymphoma is a cancer of immune cells, most commonly B cells.
Basic and translational research in the lab seeks to advance fundamental understanding of how NK cells develop, function and fight cancer. Collaborative research with the McDonnell Genome Institute (collaborators: Obi and Malachi Griffith) utilizes next-generation sequencing to identify novel mutations that can be the basis of promising therapeutic targets.
NK Cell Biology
Basic NK cell biology research efforts seek to advance our fundamental knowledge of how NK cells develop, mature, and function. These studies will provide insight into how NK cells play a role in thwarting both infectious diseases and malignant transformations. Recent examples include:
- Develop new model systems to unravel mechanisms regulating NK cell development, function, and anti-tumor effects in vivo (inducible, Ncr1-specific Cre model).
- Elucidate the role of transcription factors and microRNAs in regulating the NK cell molecular program, including a critical role for microRNA-142 in NK cell homeostasis and function.
- Define the mechanisms of innate memory-like NK cell differentiation
NK Cell Translational Research and Therapeutics
Translational research bridges and integrates basic biology and clinical therapeutics. Our goal is to take new findings about how NK cells work and apply them in pre-clinical and clinical studies.
We also investigate NK cell numbers, phenotype, and function in correlative immunology studies from patients participating in clinical trials. This allows us to better understand how immune or cellular therapies work (mechanism of action), and how to improve future clinical trial designs.
Currently, our focus is on cytokine-based therapies to enhance how NK cells from a patient or donor attack and destroy cancer cells. We are now testing memory-like NK cellular therapy to treat adult and pediatric acute myeloid leukemia patients in three separate clinical trials.
Additional studies in the lab are looking at ways to engineer memory-like NK cells with chimeric antigen receptors to direct them to new tumors with monoclonal antibodies.
Memory-like NK Cellular Therapy
Dr. Fehniger and his team discovered human cytokine-induced memory-like (CIML or ML) NK cells, after their initial identification in model organisms at Washington University. Pre-clinical work quickly followed, demonstrating that memory-like NK cells were supported by low doses of IL-2, exhibited enhanced antibody-dependent cellular cytotoxicity (ADCC), reversed the functional defects associated with uneducated NK cells, responded more effectively to myeloid leukemia targets, and ignored certain inhibitory KIR receptors. This led to the first-in-human Phase 1 clinical trial in patients with leukemia that demonstrated a safe cellular therapy with promising evidence of clinical activity and persistence of the donor NK cells in patients. These memory-like NK cells are now under investigation in 3 different clinical trials, and harnessing memory-like NK cells is a promising strategy for the cellular immunotherapy for cancer.
As a platform for safe NK cell therapy, the Fehniger group also demonstrated for the first time that memory-like NK cells engineered with chimeric antigen receptors (CAR) had improved responses compared to conventional NK cells. ML NK cells also combined with monoclonal antibodies and bi/tri-specific NK cell engagers to target these immune cells attack new types of targets, opening the investigation of memory-like cells to many different cancer.
Ongoing research is translating memory-like NK cells as a cellular therapy for various blood cancer and solid tumors.
Dr. Fehniger’s group also helped to pioneer the pre-clinical and clinical investigation of IL-15 receptor agonists as a form of immunotherapy that complements the use of therapeutic monoclonal antibodies and checkpoint blockade. Pre-clinical studies by the Fehniger group identified that IL-15 can recruit a tissue-resident NK cell population to acquire potent anti-tumor activity. In addition, IL-15 receptor agonists combined with therapeutic monoclonal antibodies to enhance anti-tumor immune responses.
Studies co-led by Dr. Fehniger at Washington University reported the first-in-human use of the IL-15 receptor agonist ALT-803/N-803 in patients who have relapsed after allogeneic hematopoietic cell transplantation. The Fehniger team leads a study of ALT-803/N-803 combined with a therapeutic monoclonal antibody (anti-CD20) for combined immunotherapy for lymphoma patients.
Lymphoma Genomics and Immunotherapy
We collaborate with the Washington University lymphoma clinical team and the McDonnell Genome Institute at Washington University to use next-generation sequencing to identify novel mutations in lymphoma patients and correlate these mutations with clinical outcomes and responses to new therapies. In addition, we have an active translational immunotherapy program seeking to develop and test new strategies to use the patient’s own immune system to treat lymphoma and related diseases.
Fehniger Lab Team
Todd A. Fehniger, MD, PhD
Melissa Berrien-Elliott, PhD
Felicia Gomez, PhD (Co-mentored)
Jennifer Foltz, PhD
Miriam Jacobs, MD
Nancy Marin, PhD
David Russler-Germain, MD/PhD
Alice Zhou, MD/PhD