WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

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The long term goals of my laboratory are to better understand the molecular programs that regulate natural killer (NK) cell development and activation, and translate basic NK cell biology into novel treatments for patients with cancer.

What are the molecular mechanisms controlling NK cell development and activation?

NK cells are innate immune lymphocytes that are important for host defense against infections and malignant transformation. NK cells require numerous cytokine signals for development, homeostasis, and activation. We and others have demonstrated that mature 'resting' NK cells in peripheral lymphoid tissues require cytokine activation to 'arm' (or 'prime') them for efficient effector functions such as cytotoxicity or cytokine production. Interestingly, multiple NK cell effector molecules appear regulated in resting NK cells at the post-transcriptional level, including perforin, granzyme B, and interferon gamma. This suggests that resting NK cells may store messenger RNAs and block their translation as a general strategy to be poised to respond once recognizing the appropriate target cell or entering a cytokine-rich inflamed environment. What is the molecular mechanism used by NK cells to mediate such a translational blockade? We are pursuing this question specifically by evaluating how two cytotoxic effector molecule mRNAs (granzyme B and perforin) are controlled in resting NK cells, and more generally by using unbiased discovery approaches (transcriptional profiling, proteomics) to define the NK cell activation program at the molecular level and identify regulatory players, including microRNAs.

NK cell based therapy for cancer

NK cells have multiple properties that make them excellent candidates as mediators of the immunotherapy of cancer, including an inherent ability to kill tumor cells and produce immunoregulatory cytokines. Our understanding of the cytokines, cell surface receptors responsible for target cell recognition, and immune cellular partners that are important for NK cells development and function has greatly advanced over the past few decades. Major challenges must be overcome to capitalize on our understanding of NK cell biology, to best utilize NK cells as a component of cancer treatment.

One major barrier to effectively using NK cells as a direct cellular therapy are challenges in generating adequate numbers of human NK cells with preserved function for dose and schedule finding clinical studies. How can NK cells be effectively expanded and activated ex vivo for the cellular therapy of hematologic malignancies? Our laboratory is working to develop a process that involves high speed cell sorting, followed by cytokine and/or accessory cell expansion to address this issue. Future endeavors will adapt this strategy for use in a clinical trial of expanded/activated NK cells as cellular therapy.

In addition, a number of new drugs have immunomodulatory properties, and may operate by augmenting NK cell function or increasing the NK cell's recognition of the cancer cell. For example, studies of anti-cancer monoclonal antibodies demonstrate that NK cells play a part in their efficacy, and highlight drug-based therapies that utilize NK cells. Another recent example is lenalidomide, a drug that augments NK cell activity in vitro and in pre-clinical models. We are currently evaluating in vitro and in vivo NK cell modulation in patients treated with lenalidomide in the context of two investigator-initiated Phase II clinical studies in relapsed/refractory classical Hodgkin lymphoma and untreated acute myeloid leukemia.

Cytokine activation results in rapid increases in granzyme B (GzmB) and perforin protein translation, and a dramatic change in NK cell morphology. (A) IL-15 activation results in the rapid translation of granzyme B and perforin protein in NK cells. NK cells at rest (0 h) or after IL-15 activation were analyzed by flow cytometry for intracellular expression of GzmB and perforin protein. (B) Resting mouse NK cells are small lymphocytes, and IL-15 activation results in dramatic morphologic changes and acquisition of cytotoxic granules.

From: Fehniger TA, Cai SF, Cao X, Bredemeyer AJ, Presti RM, French AR, Ley TJ
Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs.
Immunity 2007 Jun;26(6):798-811

Education

1994	BS (Biological Sciences with High Distinction), State University of New York (SUNY), Buffalo, NY
2000	PhD (Molecular Virology, Immunology, and Medical Genetics; Michael A. Caligiuri, advisor), The Ohio State University, College of Medicine and Public Health, Columbus, OH
2002	MD, The Ohio State University, College of Medicine and Public Health, Columbus, OH

Post-graduate Training

2002-2004	Intern and Resident, Internal Medicine, Physician Scientist Training Pathway, Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO
2004-2008	Fellow, Hematology and Oncology, Washington University School of Medicine, St. Louis, MO

Academic Appointments

2008-present

Assistant Professor, Department of Medicine, Washington University School of Medicine, St. Louis, MO

Board Certification

2006	Diplomate, American Board of Internal Medicine

National or International Awards

1996	Howard Hughes Medical Institute (HHMI) Research Fellowship for Medical Students
1999, 2001	American Society of Hematology (ASH) Travel Award
2000	American Society of Hematology (ASH) Medical Student Award
2000	American Association of Immunologists (AAI)-Huang Foundation Trainee Achievement Award
2007	American Society of Clinical Oncology (ASCO) Young Investigator Award
2007	Future Leader in Hematology Award (Celgene)
2008	American Society of Clinical Oncology (ASCO) Merit Award
2008	HHMI Physician Scientist Early Career Award

Other Awards

1990	University Honors Scholar, SUNY at Buffalo
1994	Summa cum laude, SUNY at Buffalo, Biological Sciences
1994	Phi Beta Kappa, SUNY at Buffalo
1994	Dean's Outstanding Graduate in Biological Sciences, SUNY at Buffalo
1995	J.A. Gibson Anatomical Honor Society, SUNY at Buffalo School of Medicine
1996	Edward A. Carr, Jr. Clinical Pharmacology Award, SUNY at Buffalo School of Medicine
1997	Bennett Fellowship, The Ohio State University College of Medicine
2002	Outstanding Achievement in Medical Training, Department of Internal Medicine, The Ohio State University College of Medicine
2002	Internal Medicine Research Award, Department of Internal Medicine, The Ohio State University College of Medicine
2002	Medical Scientist Award, The Ohio State University College of Medicine
2006	Siteman Cancer Center Research Development Fellowship, Washington University
2007	Siteman Cancer Center Hematopoietic Development and Malignancy Retreat Plenary Abstract Session Winner

Professional Societies

2004-present	American Society of Hematology
2004-present	American Society for Blood and Marrow Transplantation
2006-present	American Society of Clinical Oncology
2008-present	Society for Natural Immunity

Updated: August 1, 2008