WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

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My laboratory focuses on the control of graft vs. host disease using gene therapy. We have generated novel chimeric suicide genes in which the extracellular and transmembrane domains of human CD34 cDNA have been fused in frame with the entire coding sequence of the HSV-Thymidine Kinase (TK) gene. We also generated VSV-G pseudotyped Maloney-based retroviruses into which we have inserted both the parent CD34-TK fusion and a series of highly active mutants of CD34-TK (50-100 fold more active). We demonstrated that CD34 TK is expressed on the surface of transduced cells, and that the CD34 epitope can be used to affinity purify transduced T cells using FDA-approved methods of CD34+ stem cell purification. We optimized human T cell transduction (80-90% efficiency), minimized ex-vivo activation times with CD3/CD28 beads to maintain T cell alloreactivity, and optimized purification and yields of transduced human T cells (99-99.9% pure and 90-99% yield). These studies have recently been extended to the mouse, where we not only developed novel and efficient methods of transduction and selection of CD34-TK-transduced murine T cells, but also developed a murine transgenic model in which the CD34-TK transgene is being driven in the appropriate peripheral T cell compartment using the CD2 Locus Control Region. We used both transduced and transgenic T cells to develop a robust and informative series of murine allogeneic transplant models to test the role of genetically manipulated T cells and their in vivo suicide with gancyclovir on multilineage engraftment, GvHD and anti-leukemia effects. These data provided the foundation for clinical trials in human allogeneic transplant recipients that are now being planned.

Another research focus will be to identify specific genetic and epigenetic events associated with relapsed acute myelogenous leukemia. My group will focus on genetic events that may be involved in AML relapse using informative murine models of human AML, and also primary AML samples.

My other clinical/translational interests include the biology of stem cell mobilization. I am collaborating with Steven Devine and Daniel Link in both basic and clinical aspects of stem cell mobilization. The group is currently studying the effect of a novel CXCR4 antagonist, AMD3100 on stem cell mobilization in mouse preclinical studies and in human clinical trials. My other clinical and translational studies focus on clinical stem cell transplantation, leukemia and MDS clinical trials and therapy, as well as innovations in supportive care of leukemia and transplant patients. I also plan to establish a national network of GMP facilities for future clinical trials using cellular manipulations such as gene therapy.

Adhesive interactions between hematopoietic stem cells and the bone marrow microenvironment Multiple interactions between adhesion molecules tether HSCs to the stroma of the bone marrow, including CXCR4 and SDF-1, VLA-4 and VCAM-1, kit and KL, CD62 and its ligand (CD62L), and CD44 and HA. CXCR: Chemokine (C-X-C motif) receptor; HA: Hyaluronan; HSC: Hematopoietic stem cell; KL: Kit ligand; SDF: Stromal-dervied factor; VCAM: Vascular cell adhesion molecule; VLA: Very late antigen. From: Cashen AF, Nervi B, DiPersio J AMD3100: CXCR4 antagonist and rapid stem cell-mobilizing agent. Future Oncol 2007 Feb;3(1):19-27

Education

1973	BA Biology, Williams College, Williamstown, MA
1980	MD/PhD (Microbiology), University of Rochester, Rochester, NY

Post-graduate Training

1980-1981	Intern (Straight Medicine), Parkland Memorial Hospital, UT Southwestern, Dallas, TX
1981-1983	Resident, Parkland Memorial Hospital, UT Southwestern, Dallas, TX
1983-1984	Chief Resident, Parkland Memorial Hospital, UT Southwestern, Dallas, TX
1984-1987	Fellow, Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, CA

Academic Positions

1987-1988	Instructor of Medicine, Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, CA
1988-1990	Assistant Professor of Medicine, Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, CA
1990-1994	Assistant Professor of Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY
1990-1994	Director, Bone Marrow Transplant Program, Strong Memorial Hospital, Rochester, NY
1990-1994	Assistant Professor of Medicine, Hematology Unit, University of Rochester School of Medicine, Rochester, NY
1994-1997	Associate Professor of Medicine, Pediatrics and Pathology, Washington University School of Medicine, St. Louis, MO
1994-2000	Chief, Division of Bone Marrow Transplantation & Stem Cell Biology, Washington University School of Medicine, St. Louis, MO
1997-present	Professor of Medicine, Pediatrics and Pathology/Immunology, Washington University School of Medicine, St. Louis, MO
2000-2003	Acting Director, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO
2000-2006	Director, Section of Bone Marrow Transplantation & Leukemia, Washington University School of Medicine, St. Louis, MO
2000-present	Deputy Director, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
2000-present	Chief, Division of Oncology, Washington University School of Medicine, St. Louis, MO

Board Certification

1984	American Board of Internal Medicine
1987	American Board of Internal Medicine (Medical Oncology)
1988	American Board of Internal Medicine (Hematology)

Honors & Appointments

1973	BA, Magna Cum Laude, Honors in Biology, Williams College
1980	Alpha Omega Alpha, University of Rochester
1986	Special Fellow, Leukemia Society of America
1989	Junior Faculty Research Award, American Cancer Society
1992	Bauman Award, Teacher of the Year, Internal Medicine, University of Rochester
1993	Member, Editorial Board Journal of Experimental Hematology
1995	Member, Nominating Committee, International Society for Experimental Hematology
1996	Elected, American Society of Clinical Investigation (ASCI)
1997	Chairman, Nominating Committee, International Society for Experimental Hematology (ISEH)
1997	Member, Stem Cell Evaluation Committee, International Society for Hematotherapy and Graft Engineering (ISHAGE)
1997	Councilor, International Society of Experimental Hematology
1997	Recipient, Lewis T. and Rosalind B. Apple Chair in Oncology
1998	Member, Barnard Free Skin and Cancer Board of Directors
1998	Guest Editor (3 yrs), Blood Journal
1999-2006	Member, External Advisory Panel, M.D. Anderson (MDACC) PPG-AML
1999	Deputy Director, Siteman Cancer Center, Washington University School of Medicine
2000-2006	Leukemia and Lymphoma Society of America, Career Development Award Study Section Member
2000	Chairman, NHLBI Consensus Conference on Allogeneic Transplantation for Non-Malignant Diseases Bethesda, MD
2000	ISHAGE Meeting, Quebec Canada; First Prize, Scientific Merit: "Control of GvHD using genetically modified T cells"
2001	Reviewer, University of Minnesota NCI-Designated Comprehensive Cancer Center Grant (NCF)
2002-2006	Member, Board of Directors IBMTR/ABMTR
2002	Member, ASH Committee on Educational Affairs, Washington, DC
2003	Member, Board of Directors, American Society of Biology and Marrow Transplant
2003	Chairman, American Society of Biology and Marrow Transplant Council on Education and Standards
2003	NHLBI P01 Study Section Member University of Illinois, Chicago
2003	Member, Board of Directors, Barnard Free Skin and Cancer Hospital
2003-2006	Study Section Member, American Society of Hematology Faculty and Fellow Scholar Career Development Award
2004	External Advisor, Ohio State University P01 "Retrovirus Models of Lymphocyte Transformation and Disease"
2004-2009	NCI (NIH) Permanent Member CONC Study Section Member
2005	Member, Medical Advisory Board, The Bone Marrow Foundation
2005	Chairman, Study Section RFA HL-04-017 (NHLBI) Specialized Centers for Cell Based Therapy (SCCT), Annapolis, MD
2005	NIH/CSR Study Section ZRG1 - Ad Hoc Reviewer
2006-2009	Member, Clinical Oncology Study Section, Center for Scientific Review
2006	Member, K12 Advisory Committee
2006	NIH (ZRG)/CSR - Gene Therapy and Inborn Errors – Special Emphasis Review Panel
2006	Member, ASH Committee on Gene and Cell Therapy
2007	Member, Editorial Board of Clinical and Translational Science
2007	Member, Editorial Board of Clinical Medicine: Oncology
2007	Lecturer, Great Teachers Series of Medical Grand Rounds at the NIH Clinical Center in Bethesda, MD

Memberships

1991	ECOG Bone Marrow Transplant Committee
1992	International Society for Experimental Hematology
1993	American Society of Hematology
1993	American Society for Biochemistry and Molecular Biology
1993	International Society for Hematotherapy and Graft Engineering (ISHAGE)
1993	American Society for Blood and Marrow Transplantation
1996	American Society of Clinical Oncology

Updated: April 2, 2008