Bone Marrow Transplant - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

BONE MARROW TRANSPLANT A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES...

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BONE MARROW TRANSPLANT A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2004 by ICON Group International, Inc. Copyright ©2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1 Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Bone Marrow Transplant: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84358-9 1. Bone Marrow Transplant-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on bone marrow transplant. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON BONE MARROW TRANSPLANT ................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Bone Marrow Transplant ............................................................. 7 E-Journals: PubMed Central ....................................................................................................... 66 The National Library of Medicine: PubMed ................................................................................ 73 CHAPTER 2. NUTRITION AND BONE MARROW TRANSPLANT ..................................................... 121 Overview.................................................................................................................................... 121 Finding Nutrition Studies on Bone Marrow Transplant .......................................................... 121 Federal Resources on Nutrition ................................................................................................. 127 Additional Web Resources ......................................................................................................... 128 CHAPTER 3. ALTERNATIVE MEDICINE AND BONE MARROW TRANSPLANT ............................... 129 Overview.................................................................................................................................... 129 National Center for Complementary and Alternative Medicine................................................ 129 Additional Web Resources ......................................................................................................... 156 General References ..................................................................................................................... 158 CHAPTER 4. DISSERTATIONS ON BONE MARROW TRANSPLANT ................................................. 159 Overview.................................................................................................................................... 159 Dissertations on Bone Marrow Transplant ............................................................................... 159 Keeping Current ........................................................................................................................ 160 CHAPTER 5. CLINICAL TRIALS AND BONE MARROW TRANSPLANT............................................ 161 Overview.................................................................................................................................... 161 Recent Trials on Bone Marrow Transplant ............................................................................... 161 Keeping Current on Clinical Trials ........................................................................................... 183 CHAPTER 6. PATENTS ON BONE MARROW TRANSPLANT ............................................................ 185 Overview.................................................................................................................................... 185 Patents on Bone Marrow Transplant ........................................................................................ 185 Patent Applications on Bone Marrow Transplant..................................................................... 190 Keeping Current ........................................................................................................................ 196 CHAPTER 7. BOOKS ON BONE MARROW TRANSPLANT ............................................................... 199 Overview.................................................................................................................................... 199 Book Summaries: Federal Agencies............................................................................................ 199 Book Summaries: Online Booksellers......................................................................................... 200 Chapters on Bone Marrow Transplant ...................................................................................... 201 CHAPTER 8. MULTIMEDIA ON BONE MARROW TRANSPLANT..................................................... 205 Overview.................................................................................................................................... 205 Audio Recordings....................................................................................................................... 205 CHAPTER 9. PERIODICALS AND NEWS ON BONE MARROW TRANSPLANT.................................. 207 Overview.................................................................................................................................... 207 News Services and Press Releases.............................................................................................. 207 Newsletter Articles .................................................................................................................... 210 Academic Periodicals covering Bone Marrow Transplant......................................................... 210 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 211 Overview.................................................................................................................................... 211 U.S. Pharmacopeia..................................................................................................................... 211 Commercial Databases ............................................................................................................... 212 Researching Orphan Drugs ....................................................................................................... 213 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 217 Overview.................................................................................................................................... 217 NIH Guidelines.......................................................................................................................... 217

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NIH Databases........................................................................................................................... 219 Other Commercial Databases..................................................................................................... 221 APPENDIX B. PATIENT RESOURCES ............................................................................................... 223 Overview.................................................................................................................................... 223 Patient Guideline Sources.......................................................................................................... 223 Associations and Bone Marrow Transplant .............................................................................. 229 Finding Associations.................................................................................................................. 230 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 233 Overview.................................................................................................................................... 233 Preparation................................................................................................................................. 233 Finding a Local Medical Library................................................................................................ 233 Medical Libraries in the U.S. and Canada ................................................................................. 233 ONLINE GLOSSARIES................................................................................................................ 239 Online Dictionary Directories ................................................................................................... 240 BONE MARROW TRANSPLANT DICTIONARY ................................................................. 241 INDEX .............................................................................................................................................. 319

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with bone marrow transplant is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about bone marrow transplant, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to bone marrow transplant, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on bone marrow transplant. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to bone marrow transplant, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on bone marrow transplant. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON BONE MARROW TRANSPLANT Overview In this chapter, we will show you how to locate peer-reviewed references and studies on bone marrow transplant.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and bone marrow transplant, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “bone marrow transplant” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Long-Term Oral and Craniofacial Complications Following Pediatric Bone Marrow Transplantation Source: Pediatric Dentistry. 22(1): 57-62. January-February 2000. Contact: Available from American Academy of Pediatric Dentistry. Publications Department, 211 East Chicago Avenue, Suite 700, Chicago, IL 60611-2616. Summary: Bone marrow transplantation (BMT) has become a common form of treatment for childhood diseases and disorders that directly or indirectly affect the production of stem cells which give origin to blood and immune system elements. The pre transplant treatment regimens can include, but are not limited to, chemotherapy or radiation therapy, both of which can cause considerable acute and long term undesired

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Bone Marrow Transplant

effects in the oral cavity and the craniofacial complex. This article discusses the complications that a pediatric dentist may encounter when treating a child or adolescent who has undergone BMT. Systemic effects of BMT can include immunologic dysfunction, pulmonary dysfunction, endocrine dysfunction (leading to growth and development problems), and central nervous system abnormalities (neuropsychological deficits, lower IQ scores, problems with visual motor, fine motor, abstract thinking, and spatial processing tasks). The authors focus on the role of dental care, chronic oral graft versus host disease (GVHD), xerostomia (dry mouth) and taste dysfunction, infections, non gingival (gum) soft tissue growths, dental hypersensitivity, and dental and craniofacial developmental abnormalities. The authors stress the importance of the dentist's role in discussing these possible sequelae with the patient and his or her caregivers, as many physicians are not aware of these potential problems and may not inform the family. With this information, the patient and caregivers become aware of the importance of good oral and dental care in decreasing the chances of oral complications. 6 figures. 44 references. •

Oral Cavity Complications of Bone Marrow Transplantation Source: Seminars in Cutaneous Medicine and Surgery. 16(4): 265-272. December 1997. Summary: Bone marrow transplantation, once regarded as experimental, has evolved into a standard treatment for a variety of malignancies. Considerable advances have been made in histocompatibility typing, pretransplantation chemotherapy, and posttransplantation immunosuppressive therapy, as well as prophylaxis and treatment of infections. This article reviews the oral cavity complications that may result from bone marrow transplantation. The authors note that oral complications develop in almost all patients, and their early recognition may result in the institution of prompt treatment and prolonged survival. Mucositis, often severe and extremely painful, develops in more than three quarters of bone marrow transplant recipients, and its prevention, unfortunately, remains unsatisfactory. Herpes simplex virus and Candida albicans account for most oral infections, although their incidence has been dramatically reduced by the institution of prophylactic agents. Graft versus host disease (GVHD) continues to be a significant complication of marrow transplantation, and the detection of commonly occurring oral changes may support its diagnosis. The authors conclude with a discussion of the prevention options available for these patients. 4 figures. 47 references. (AA-M).

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Changes in the Periodontal Status of Patients Undergoing Bone Marrow Transplantation Source: Journal of Periodontology. 71(3): 394-402. March 2000. Contact: Available from American Academy of Periodontology. Suite 800, 737 North Michigan Avenue, Chicago, IL 60611-2690. (312) 573-3220. Fax (312) 573-3225. Summary: Patients receiving an HLA matched bone marrow transplant (BMT) from a relative or unrelated donor undergo a permanent alteration of their immune system, followed by a prolonged period of immunodeficiency. This article reports on a study that examined alterations in the periodontal status of patients for the 6 months post bone marrow transplantation. Patients scheduled for BMT (n = 37) participated in the study. One examiner carried out periodontal examinations (clinical and radiographic) immediately prior to 3 and 6 months after transplantation. All patients followed an intense oral care program. Subgingival (under the gum) plaque samples were analyzed by ELISA for the presence of pathogens, including Porphyromonas gingivalis,

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Actinobacillus actinomycetemcomitans, and Prevotella intermedia. Gains in clinical attachment level (CAL) at 4 or more sites from baseline to 6 months post BMT were noted in 9 of 16 patients (56 percent), while 6 of 16 patients (38 percent) experienced a loss of CAL at 4 or more sites in the same period. A significant improvement in the gingival index occurred between all sequential time periods when assessed at a site level. At a patient level, 11 of 18 patients (61 percent) showed a significant change in gingival index between baseline and 3 months, and 10 of 16 patients (63 percent) between baseline and 6 months. There was no significant relationship between clinical changes and the prevalence of the periodontal pathogens at the various time periods. The authors conclude that an improvement in periodontal health was recorded between baseline and 6 months post transplantation. Most of the improvement in periodontal status was noted in the first 3 months after BMT, with a slight decline in periodontal health between 3 and 6 months posttransplant. This improvement was noted despite the profound changes occurring in the immune system. No significant alteration was noted in the prevalence of periodontal pathogens during the study period. The results of this study highlight the benefits of a stringent oral health care protocol as evidenced by the improvement of periodontal health in the BMT patients despite profound immunosuppression. 5 figures. 3 tables. 48 references. •

Bone Marrow Transplants: Current Applications and Implications for Oral Health Source: New York State Dental Journal. 65(4): 28-31. April 1999. Contact: Available from Dental Society of the State of New York. 7 Elk Street, Albany, NY 12207. (518) 465-0044. Summary: The application of bone marrow transplantation (BMT) to address a variety of pathologies has increased dramatically in the last decade. Side effects of BMT include a variety of documented untoward effects on oral health, many of which are age dependent. With the increasing number of people, particularly children, receiving BMT, it is entirely possible that these recipients may appear as 'routine, healthy' patients in a general practice or other oral health care setting. This article reviews the treatment modality of BMT, its current applications, and the short and long term effects that the oral health care practitioner must identify, understand, and address. Diseases treated with BMT include bone marrow disorders, malignancies, metabolic diseases, inherited disorders, and severe combined immunodeficiencies. Oral complications in pediatric MBT patients can include mucositis and ulcerations, salivary flow decrease and compositional change, xerostomia (dry mouth), caries (cavities) rate increase, and oral infections. The authors stress that preventing oral problems in patients who have undergone BMT is critical. 2 tables. 6 references. (AA-M).

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Guidelines for the Management of Pediatric Dental Patients Receiving Chemotherapy, Bone Marrow Transplantation, and/or Radiation Source: Pediatric Dentistry. 20(6): 53-54. November 1998. Contact: Available from American Academy of Pediatric Dentistry. Publications Department, 211 East Chicago Avenue, Suite 700, Chicago, IL 60611-2616. Summary: The pediatric patient who is beginning, currently receiving, or has received chemotherapy, a bone marrow transplant (BMT), or radiation requires special consideration and altered oral and dental treatment schemes due to the systemic impact of any of these cancer treatments. This Guideline, published by the American Academy of Pediatric Dentistry (revised in 1993), summarizes the guidelines for the management of these patients. Since there are a myriad of protocols for chemotherapy, BMT, and

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radiation, oral and dental care must be provided in consultation with the oncologist and tailored to the individual needs of the patient. The Guideline offers five management objectives: decrease the morbidity and mortality due to infection; decrease the morbidity due to hemorrhage; facilitate the patient's nutritional status; improve the patient's comfort; and increase the education of the patient, family, and physician relative to the importance of maintaining oral health and the methods to achieve it. The Guideline then divides management of the pediatric cancer patient into three phases of care. For each phase (pretreatment, during treatment and immediate posttreatment, and long term followup), the Guideline reviews assessment, diagnosis, and treatment. The long term followup phase also addresses hematologic guidelines and antibiotic prophylaxis guidelines. •

Gastrointestinal and Nutritional Sequelae of Bone Marrow Transplantation Source: Archives of Disease in Childhood. 75(3): 208-213. September 1996. Contact: Available from Archives of Disease in Childhood. Subscription Manager, BMA House, Tavistock Square, London WC1H 9JR, England. Summary: This article outlines the gastrointestinal (GI) and nutritional sequelae of bone marrow transplantation. The authors note that the nature of the GI injury following bone marrow transplantation and its clinical and nutritional sequelae are poorly defined. The authors report on a study in which prospective assessments of GI function, nutritional status, and well-being were carried out in 47 patients (28 males, 19 females; mean age 8.4 years) undergoing bone marrow transplant. Thirty-one episodes of diarrhea occurred in 27 patients at a median of 10 days after transplantation. Ninety-one percent of episodes were associated with protein losing enteropathy. Protein losing enteropathy was more severe in graft-versus-host disease (GVHD) compared with other causes. Transient pancreatic insufficiency developed in 18 patients, and pancreatitis in one. Intestinal permeability was normal in 12 patients who had no diarrhea during the conditioning treatments. Patients with diarrhea had a significantly greater decrease in nutritional status and well-being than patients without diarrhea. The authors conclude that GI injury following bone marrow transplantation is complex and has profound effects on nutritional status and well being of the patients. 5 figures. 1 table. 39 references. (AA-M).

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Bone Marrow Transplant Nephropathy: A Case Report and Review of the Literature Source: JASN. Journal of the American Society of Nephrology. 8(1): 166-173. January 1997. Summary: This article presents a case of bone marrow transplant nephropathy, including a review of the clinical and pathologic features. Bone marrow transplantation can be complicated by renal failure resulting from a variety of causes. Early renal injury most often results from infection and its subsequent treatment with nephrotoxic medications. Late renal injury after bone marrow transplantation is characterized by a syndrome similar to the hemolytic uremic syndrome. This renal syndrome, called 'bone marrow transplant nephropathy,' is thought to evolve from the late effects of radiation therapy and cytotoxic chemotherapy on the kidney. The histopathology is characterized by mesangiolysis with focal aneurysmal dilatation, fibrin thrombi in capillary loops, and marked widening of the subendothelial space resulting from deposition of amorphous material, similar to the appearance of radiation nephritis. No definitive treatment is currently available for bone marrow transplant nephropathy, except for supportive

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therapy. One table summarizes adult and pediatric cases of bone marrow transplant nephropathy. 2 figures. 5 tables. 26 references. (AA-M). •

Dental Evaluation in Bone Marrow Transplantation Source: General Dentistry. 43(4): 369-371. July-August 1995. Summary: This article presents a case report that demonstrates the importance of thorough presurgical dental radiographic and clinical examinations in bone marrow transplantation. The authors stress that general dentists should become familiar with the procedure of bone marrow transplantation (BMT) and their potential role in the success of this technically simple but immunologically complex treatment. Dentists have three roles: pretransplant oral evaluation and treatment of existing and potential dental infections; inpatient treatment of oral complications during immunosuppression and graftings; and long-term prevention and management of posttransplant dental complications. The case report describes the case of a 38-year-old woman who needed dental restorative work performed before her BMT procedure could be approved. The authors reiterate the importance of dentists understanding the implications of BMT and the need to eliminate all potential dental infection before the procedure. In the case presented, thorough radiographic and clinical examinations would have precluded misinforming the patient and prevented a six-week delay of the bone marrow transplant. 1 figure. 8 references. (AA-M).

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Long-Term Effects of Bone Marrow Transplantation on Dental Status in Children with Leukaemia Source: Bone Marrow Transplantation. 20(10): 865-869. November 15, 1997. Summary: This article reports on a study of the dental status of 27 children (19 males and 8 females) with leukemia, with the aim of studying the oral and dental health in long term survivors after bone marrow transplantation (BMT). The children were followed up with a routine oral examination, panoramic tomogram and, when necessary, an endoral radiograph at a median range of 2 years after BMT. Community periodontal index treatment necessity (CPITN), dental caries, missing or filled permanent teeth (DMFT), and dento-facial alterations according to World Health Organization criteria were registered and evaluated. Median age of the patients at BMT was 9 years (range 1.1 to 17.9 years). The mean DMFT score ranged from 1.6 to 12.4 according to age at examination and was slightly higher than the rate reported in children who received chemotherapy alone. CPITN showed the presence of soft deposits in 77.7 percent, serious gingivitis in 59.2 percent, and parodontal involvement in 3.7 percent of cases. Dento-facial abnormalities were found in 55.5 percent of patients, while 62.9 percent of the patients had tooth abnormalities or agenesis. Nine out of 27 patients (33 percent) had root hypoplasia. A negative impact on DMFT index due to multiple post-BMT factors was found. The authors conclude that age is the crucial factor in determining a developmental defect of enamel and root. The follow up of long term survivors after BMT should include regular dental examination. 1 figure. 3 tables. 26 references. (AA-M).

Federally Funded Research on Bone Marrow Transplant The U.S. Government supports a variety of research studies relating to bone marrow transplant. These studies are tracked by the Office of Extramural Research at the National

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Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to bone marrow transplant. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore bone marrow transplant. The following is typical of the type of information found when searching the CRISP database for bone marrow transplant: •

Project Title: A NOVEL APPROACH TO PREVENT GRAFT-VERSUS HOST DISEASE Principal Investigator & Institution: Mcclure, G D.; Apoimmune, Inc. 1044 E Chestnut St Louisville, Ky 40204 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 31-OCT-2002 Summary: (provided by the applicant): Bone marrow transfusion (BMT) holds the potential to cure many blood diseases. However, BMT recipients often develop graftversus-host disease (GvHD), a life-threatening condition in which immune cells from the infused transplant attack the recipient's tissues. Current treatments using nonspecific immunosuppressants have limited effectiveness. Moreover, there is no clinically proven method of preventing GvHD. We have developed a therapy that can prevent GvHD. In this therapy we place a recombinant protein, mFasL, on the surface of immune cells in the graft to target these cells for destruction. It is superior to current treatments since it can prevent GvHD. Another variant of our therapy can cure existing GvHD without using nonspecific immunosuppressants. During this project we will produce more mFasL and show that it can prevent or cure GvHD in vivo. In the longer term, once in vivo efficacy is shown, we will develop and market a therapeutic biologic based on mFasL. Use of the biologic will lower mortality and morbidity associated with GvHD and allow BMT to be used much more routinely in the clinic. The long-term success of this project will expand therapeutic use of BMT to cure blood diseases and to prevent allograft and xenograft rejection. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: A SEARCH FOR GENES THAT REGULATE STEM CELLS Principal Investigator & Institution: Weissman, Irving L.; Professor; Pathology; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-SEP-1997; Project End 31-AUG-2007 Summary: Hematopoietic stem cells (HSC) are the cells responsible for perpetual production of blood cells in the body, and the only cells in a bone marrow transplant that provide sustained hematopoiesis. The unique property of self renewal enables HSC,

2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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in the steady state, to maintain a constant number of HSC and, in states of stress, allows them to expand their numbers by symmetric self-renewing divisions. In the first phase of this grant, we set into place a diverse set of searchers for the genes that are responsible for stem cell self-renewal. These studies revealed a strong candidate pathway involving Wnt, beta-catenin and axin; a second pathway involving Bmi-2; several other candidate genes selectively expressed in self-renewing HSC, and the unpaired/domeless-JACK-STAT pathway that specifies self-renewal in the drosophila male germ line. Here the 4 collaborating labs continue the search for the complete set of expressed genes that govern HSC behaviors including self-renewal, avoidance of apoptosis, differentiation to downstream myeloid or lymphoid lineages, and the decision to leave the bone marrow to circulate. We also introduce the use of a massive parallel sequencing (MPSS) effort to get the complete transcriptomes of LT-HSC, STHSC/MPP, CLP and CMP to allow electronic analyses and subtractions. We also concentrate efforts not only to continue a deep examination of the Wnt/beta?catenin signal transduction pathway (a pathway activated in oncogenesis) by quantitative methods of proteomics and system perturbation, but also the genes translocated in leukemias that have acquired the capacity to self-renew. Candidate genes identified from the library and microarray studies will be screened rapidly for function by transduction of native resting HSC with regulatable lentiviral vectors and tested in vivo and in vitro for effects on HSC numbers and functions. We continue the Drosophila genetic approach for identification of more extrinsic (hub cell) and intrinsic genes regulating spermatogenic stem cells, as well as using epistasic assays to clarify interacting gene expression networks. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ABI-ABI SIGNALING IN NEOPLASTIC HEMATOPOIESIS Principal Investigator & Institution: Dai, Zonghan; Medical Oncology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): The overall objective of this proposal is to delineate the mechanisms associated with Bcr-Abl-induced leukemogenesis. Previous studies have identified two Abl interactor (Abi) proteins, Abi-1 and Abi-2, that bind to cellular Abl (c-Abl) and are substrates of Abl tyrosine kinase. Abi-1 is tyrosine-phosphorylated in hematopoietic cells transformed by Bcr-Abl. Recent studies indicate that Abi-1 is a key regulator of Rac signaling, a pathway important for regulation of hematopoietic cell migration and homing. Abi-2, on the other hand, is degraded in Bcr-Abl-expressing hematopoietic cells. The expression of Abi-2 is lost in cell lines and bone marrow cells isolated from patients with aggressive Bcr-Abl-positive leukemia. This proposal is based on the hypothesis that the signal transduction from Bcr-Abl to Abi-1 and Abi-2 may play an important role in Bcr-Abl-induced leukernogenesis. We postulate that the tyrosine phosphorylation of Abi-1 and subsequent activation of Rac pathway may represent an important mechanism by which Bcr-Abl induces abnormalities of cytoskeletal function and metastatic phenotype in leukemic cells. We believe that loss of Abi-2 may be a component in the progression of Bcr-Abl-positive leukemia. The goals of this proposal, therefore, are to examine the leukemogenic potential of a mutant Bcr-Abl that is defective in signaling to Abi-1 and Abi-2; to determine the role of Abi-1 and Abi-2 in Bcr-Abl-induced leukemogenesis; and to define the mechanisms by which Bcr-Abl regulates Abi signal transduction. To achieve these goals, biochemical and genetic approaches are designed to disrupt or inactivate signal transduction of Abi-1 and Abi-2 in hematopoietic system. Bone marrow transplant mouse models will be employed to

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evaluate the effect of disruption of Abi signaling on Bcr-Abl-induced leukemogenesis. Sequences in Abi-1 and Abi-2 that are critical for regulation of signal transduction will be defined and mutations wilt be made for functional analysis. Collectively, these studies may provide insight into the regulatory mechanisms of cell migration, homing, and metastasis. Understanding the role of Abi signaling in neoplastic hematopoiesis should shed light on development of more effective therapies for the treatment of human leukemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALLOSPECIFIC IMMUNOREGULATORY T CELLS IN BMT RECIPIENTS Principal Investigator & Institution: Truitt, Robert L.; Professor; Pediatrics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532264801 Timing: Fiscal Year 2002; Project Start 20-AUG-2001; Project End 31-JUL-2004 Summary: (provided by applicant): Distinct and identifiable populations of regulatory T cells control the physiological outgrowth and function of autoreactive cells in peripheral tissues. In animal models, loss or dysfunction of regulatory T cells can lead to autoimmune disease. We have identified a unique population of thymus-derived T cell receptor (TCR)+, CD4+ regulatory T cells in murine models of allogeneic bone marrow transplantation (BMT) and donor leukocyte infusion (DLI) therapy that specifically suppress the GVH reactivity of donor T cells. These cells may help establish and maintain peripheral tolerance to host and donor antigens. Regulatory TCR+ CD4+ T cells from DLI-treated mice suppress alloreactivity in an alloantigen-specific manner in vitro and GVH disease after adoptive transfer in vivo. We hypothesize that similar regulatory T cells emerge from the human thymus post-transplant, but that diminished capacity to generate regulatory T cells (due to age, prior chemotherapy, radiation, etc.) contributes to a higher risk of GVH disease after DLI therapy and, possibly, to the onset of chronic GVH disease. Quantitative measurements of TRECs in combination with unique phenotypic markers now allow for a definitive assessment of the kinetics and extent of the thymic contribution to post-transplant immune reconstitution in humans. Using these techniques, we propose to identify and isolate human regulatory T cells in the high TREC-expressing recent thymic emigrant (RTE) population and correlate their presence (or absence) with clinical outcome after allogeneic BMT (with or without DLI therapy). The purpose of this R21 exploratory grant is to generate data in humans that supports our hypothesis and validates the extension of observations made in preclinical models to human BMT. Thymic regulatory T cells may be critical to the success of DLI therapy without GVH disease as well as to the successful induction of tolerance by costimulatory blockade. We propose to determine: (a) whether regulatory T cells can be detected within the population of RTE cells in the peripheral blood of human recipients of HLA-disparate BMT; (b) whether regulatory T cells can be induced and expanded ex vivo from the peripheral blood of BMT patients for possible use in adoptive transfer protocols to prevent GVH disease, and (c) whether induction of anergic T cells by costimulatory blockade ex vivo induces allospecific regulatory cells in either the BMT patient or the donor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANIMAL MODEL TO STUDY THE ROLE OF CYTOTOXICITY IN GVHD Principal Investigator & Institution: Levy, Robert B.; Professor of Immunology; Microbiology and Immunology; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 30-SEP-1996; Project End 31-AUG-2005 Summary: (Adapted from the applicant's abstract): The overall focus of the proposed studies in this application is to determine how cytotoxic function following allogeneic bone marrow transplantation influences the outcome of the transplant. Experiments will address related questions utilizing cytotoxically defective donor strains of mice. Single (i.e., perforin or CD95L = csd) and double cytotoxic deficient (cdd) strains will be employed to assess the role of donor cytotoxic function in GVH responses contributing to progenitor cell engraftment and GVH disease using experimental BMT models involving MHC mismatched and minor histocompatibility antigen mismatch donor/recipient combinations. Studies are designed to generate mouse strains deficient in tumor necrosis factor receptor-1 and/or 2 expression to be used to establish an allogeneic BMT model lacking three major effector pathways mediating cytotoxicity. These models will be used to analyze GVHD induced weight loss, clinical signs, tissue damage and immune deficiency. The use of CD4+ and CD8+ T cell subsets in this model will be of interest to determine if the "subtraction" of these effector pathways differentially affects their capacity to induce GVH responses. The "triple deficient" model can subsequently be used for the design of experiments to address the potential contribution of additional cytotoxic pathways involving TWEAK and TRAIL dependent signaling. These approaches will permit further testing of the hypothesis that differing effector molecules play more and less important roles in differing GVHD target compartments. Finally, experiments are proposed to examine the potential application of infused recipient (i.e., syngeneic) populations to kill donor cells following BMT to inhibit or reverse ongoing GVHD. Cell populations to be examined will include cytotoxic T cells and antigen presenting cells transduced with death receptor ligands. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AZOLE-RESISTANT CANDIDA IN MARROW TRANSPLANT PATIENTS Principal Investigator & Institution: Marr, Kieren A.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BEHAVIORAL EFFECTS OF CANCER AND ITS TREATMENT Principal Investigator & Institution: Redd, William H.; Professor and Associate Director; Ruttenberg Cancer Center; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: Description (adapted from investigator's abstract): The proposed research investigates longitudinal determinants of distress among mothers of children undergoing bone marrow transplant (BMT) in the treatment of pediatric cancer. Data would be collected from up to 509 mothers during 5 structured interviews to occur at 2-

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weeks before BMT, immediately before BMT, and 6, 12, and 18 months post BMT. The proposed work would be guided by a conceptual integration of research in the areas of parental responses to BMT, cognitive/social processing of negative life events, and the impact of dispositional characteristics and prior stressful life events on adjustment to a severe negative life event. Stated aims are to 1) examine the longitudinal course of distress in the mothers of children undergoing BMT; 2) determine the role of cognitive and social processing in the development and maintenance of mothers' distress during and after BMT; and 3) assess how dispositional optimism, monitoring coping style, and prior negative life events influence mothers' cognitive and social processing of their distress after BMT. The proposed data analysis consists of latent growth curve and structural equation modeling. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BLOOD AND MARROW TRANSPLANT CLINICAL RESEARCH NETWORK Principal Investigator & Institution: Appelbaum, Frederick R.; Director; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 05-JUN-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The objective of this grant application is to become one of the core clinical centers in the proposed Blood and Marrow Transplant Clinical Research Network. There are a number of features of the Fred Hutchinson Cancer Research Center (FECRC) Marrow Transplant Program that make it an attractive candidate for inclusion in the Network. First, we have maintained a large, stable transplant program for several decades transplanting between 450 and 550 patients per year with excellent clinical outcomes. Thus, we have access to a relatively large number of patients. Second, our group includes a large number of investigators focused on the general topic of transplantation. This group is supported by seven P0ls and 23 R0ls, and last year published 142 papers on the topic. Thus, our inclusion will help assure a source of possible studies for future testing in the Transplant Network. Third, our program is deeply committed to cooperative clinical research. For example, last year 231 of 451 patients transplanted in Seattle (51%) were entered onto multi-institutional trials. Finally, the FHCRC provides an outstanding environment in which to conduct the sorts of studies described, with state-of-the-art clinical and laboratory facilities. The proposed Blood and Marrow Transplant Clinical Research Network has the potential to facilitate studies leading to substantial improvements in the outcome of transplantation. Inclusion of the Fred Hutchinson Cancer Research Center in this network should help it achieve this goal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BLOOD VS. BONE MARROW STEM TRANSPLANT Principal Investigator & Institution: Djulbegovic, Benjamin M.; Associate Professor of Medicine; Internal Medicine; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Peripheral blood stem cells (PBSC) are used increasingly as an alternative to bone marrow (BM) as a source of stem cells for allogeneic (allo) transplantation in the management of hematologic malignancies. This shift in practice was based on the results of several small randomized controlled trials (RCTs), which indicated possible survival and disease-free survival advantages of PBSC

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over BM transplant (T). However, some trials showed that the use of PBSC is linked to higher levels of graft versus host disease, which in turn can compromise the survival of patients who received PBSC. Since these small trials could not individually achieve conclusive results about the relative effects of PBSC vs. BM transplant, substantial controversy about a possible advantage of PBSCT over BMT on mortality and disease free survival exists. This is a classic situation when the techniques of the systematic review (SR), aimed at assembling the totality of the evidence on the relative benefit and risks of the use of allogeneic PBSCT or BMT, should be used to solve this controversy and existing disagreement. Indeed, we recently performed such a systematic review with a meta-analytic (MA) quantitative summary to show that in comparison with alloBMT, allo-PBSCT leads to better overall survival, less transplant related deaths, fewer relapses and prolonged disease free survival. We like to note here that by combining existing data sets, using a technique of SR/MA, we were able to demonstrate what none of the individual study was able to do: PBSCT is superior to BMT for the most of clinical outcomes. However, our study was based on the data extracted from the published studies. This is known to be an inferior type of SR/MA and may not provide definitive evidence. The gold-standard method to combine the totality of existing evidence is to perform individual patient data meta-analysis (IPD MA). Thus, by collecting individual patient data (from the existing data sets), we will be able to focus on the following objectives: 1. Is allo-PBSCT superior to allo-BMT in the management of hematological malignancies for a number of clinical end-points, including overall mortality, transplantrelated mortality, relapse rates, disease-free survival, incidence of acute and chronic graft-versus-host disease (GVHD), incidence of chronic. Since some retrospective studies suggest that PBSCT may be more effective in hematological malignancies with a poor risk, while BMT may be more beneficial for the patients with good risk malignancies, we will test the following hypothesis: 2. Is there a subgroup of patients for whom BMT is superior to PBSCT? The technique of IPD MA is an ideal method to perform a subgroup analysis. Finally, since the main expected differences in outcomes might be the result of a different composition of allo-graft, we will test an additional hypothesis: 3. Is there a relationship between the composition of the graft (e.g. number of CD3 cells, number of CD34 cells) and the probability of development of acute and chronic GVHD? 4. Is there an effect of the GVHD prophylaxis regimen on the development of acute or chronic GVHD? Using IPD from studies that utilized different prophylaxis regimens it may be possible to test the interaction of GVHD prophylaxis among these studies. We will test all these hypotheses by collecting individual-patient data on each outcomes of interest from the existing data sets (i.e. from published and unpublished randomized studies) using the techniques of SR/MA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BONE MARROW TRANSPLANT (BMT) SURVIVORS STUDY Principal Investigator & Institution: Bhatia, Smita; City of Hope National Medical Center Duarte, Ca 91010 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2003 Summary: (Adapted from the Applicant's Abstract): Through collaboration between the City of Hope National Medical Center and the University of Minnesota, we propose to define a cohort of patients who have undergone bone marrow transplantation (BMT) at these two centers and have survived at least two years, regardless of their current lifestatus. The objective of this Bone Marrow Transplant Survivors' Study (BMT-SS) is to establish and characterize a cohort of 1,894 pediatric and adult long-term survivors of BMT, to address the following aims: i) Identify detailed information on the incidence

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and risk factors for cardiopulmonary disease, endocrine abnormalities, fertility, and subsequent cancers; ii) Describe the impact of the above complications on the quality of life in this cohort of BMT survivors; iii) Characterize the health-related behaviors and patterns of medical care in survivors. The methodology involves a mailed survey of two questionnaires: (i) the BMT-SS Questionnaire, a validated, self-administered (subjects > 18 years) or parent-administered (subjects 18 years) or the Child's Health Questionnaire (subjects < 18 years). A frequency-matched sample of 500 siblings will be enrolled into the study. The sibling controls will provide: i) the ability to make direct comparisons with the survivors, ii) data on outcomes in a noncancer population, not available from other sources (vital statistics, NHIS, etc.). For selected reported outcomes (second cancers, etc.) we will conduct additional analyses using a nested case-control approach. This will allow us to collect additional, more extensive data on survivors experiencing the outcomes (cases), and those not experiencing the outcome (controls). The cohort will be of sufficient size and heterogeneity with respect to primary malignancy, type of transplant age at transplant, and ethnic background to allow for the study of endpoints of interest in this population. The results will provide important information that may be used in the design of future therapeutic strategies and/or interventions to decrease the occurrence of deleterious effects related to treatment exposures and host factors. Having such a cohort in place will give us the opportunity in the future to continue to collect information on major study end-points (e.g., second cancers, births, cardiac complications, etc.) that may have occurred since the completion of the initial questionnaire. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BONE MARROW TRANSPLANT CLINICAL NETWORK Principal Investigator & Institution: Stadtmauer, Edward A.; Associate Professor of Medicine; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: This project is part of a Blood and Marrow Transplant Clinical Research Network which is conducting multicenter clinical trials in hematopoietic stem cell transplantation. The purpose of the network is to promote the efficient comparison of novel treatment methods and management strategies of potential benefit for children and adults undergoing blood or marrow transplantation. Studies under development include a comparison of blood versus marrow stem cell transplantation. Studies under development include a comparison of blood versus marrow stem cell transplantation after marrow ablation, the development of non-myeloablative transplant regimens, and the best ways to avoid infections in transplant patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CANCER AND LEUKEMIA GROUP B Principal Investigator & Institution: Crawford, Jeffrey; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 31-MAR-2003 Summary: (adapted from the applicant's abstract): Duke Medical Center is currently completing its second five year grant cycle as a member of Cancer and Leukemia Group B (CALGB). Throughout Duke's involvement with CALGB, this institution has consistently been one of the top institutions in overall patient accrual and specifically has been one of the leading institutions in patient accrual from a main member

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institution. Over the period of the last grant cycle, Duke has developed an affiliate program through the Duke Oncology Consortia (DOC) which involves cancer centers and hospitals throughout the Southeast United States. This affiliate membership is still growing in number of sites and level of participation in clinical trials. In addition, the Duke Oncology OutReach Services (DOORS) network provides onsite cancer care at small hospitals and clinics in neighboring counties. Both intramural and extramural clinical trial participation are coordinated through centralized clinical trials offices at Duke. This includes personnel support for core administrative functions, clinical trial coordination provided by disease and modality specific clinical research nurses, and data management and follow-up by dedicated CALGB data managers. This organizational structure is further strengthened by close interaction with the CALGB biostatistics and data management center under the direction of Dr. Stephen George who is also director of biostatistics for the Duke Cancer Center, Scientifically, Duke has active cadre members in all the disease and modality related CALGB committees. Duke investigators serve as study chairs on Phase III trials in AML, stage IV breast cancer, the national high priority trial of bone marrow transplant in the adjuvant treatment of breast cancer patients (9082), as well as numerous Phase II studies. Duke is also a center for Phase I studies for pharmacology/experimental therapeutics. This has been further strengthened by the recruitment of Dr. Michael Colvin to become Director of the Cancer Center. Furthermore, Dr. Harvey J. Cohen, Director of the Aging Center has become an active member of CALGB and was instrumental in the formation and leadership of a working group evaluating cancer and aging. The recruitment of Dr. David Harpole in Thoracic Surgery, led to Duke becoming a major site for participation in CALGB surgical trials. Multimodality support has also been provided by active participation from other members of surgical oncology as well as radiation oncology, pathology, and correlative sciences. Areas of expansion by Duke investigators within CALGB over the next grant cycle will be particularly targeted to multimodality trials, Phase I studies, bone marrow transplant trials, and the continued participation in ongoing phase II and III trials. In addition, our participation in community trials addressing minority issues, gero-oncology, and cancer control will expand with the participation of Dr. Barbara Rimer and Dr. Colleen McBride. As a leading institution in CALGB activities over the last decade, Duke is looking forward to funding support appropriate to our current and anticipated level of patient accrual and scientific involvement in CALGB trials during the next grant cycle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CANCER CENTER CALGB PARTICIPATION Principal Investigator & Institution: Muss, Hyman B.; Professor of Medicine; Vermont Regional Cancer Center; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405 Timing: Fiscal Year 2002; Project Start 20-APR-1998; Project End 31-MAR-2003 Summary: (adapted from the applicant's abstract): The Vermont Cancer Center (VCC), an NCI designated Comprehensive Cancer Center, joined the CALGB in 1995. In that short time the VCC has made significant headway in becoming a major participant in CALGB activities. Eight VCC members have made major commitments to supporting CALGB efforts. Dr. Hyman Muss continues to be extremely active in CALGB and serves as the Co-Chair of the Working Group for the Elderly and the Vice Chair of the Breast Cancer Committee, in addition to chairing two CALGB protocols (8869 and 9670). Dr. Steven Grunberg, a member of the Clinical Economics Committee, is currently developing a clinical protocol that will compare cost with symptom control for

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antiemetics. Dr. David Krag is an active member of the Breast Core Committee and is helping CALBG develop a protocol for sentinel node staging for women with early stage breast cancer. Dr. Seth Harlow will assume Dr. Krag's role as member of the Surgery Committee. Dr. Donald Weaver participates extensively in pathology group activities and has a major interest in breast cancer. Drs. Michael Cooper, Barbara Grant, and Richard Branda have major interest in urologic cancer, leukemia and lymphoma, and nutrition and cancer, respectively, and have developed concepts for CALGB clinical investigations. The development of multidisciplinary, disease-site oriented, affinity groups within our Center has established major liaisons between laboratory and clinical scientists. This will strengthen our institutional commitment to the group and allow VCC members to develop innovative companion trials for the CALGB. Recently, Drs. Grant and Branda presented two concepts-one related to assessing the importance of folate status on chemotherapy toxicity in women with early breast cancer, and a second that utilizes a novel reporter gene (hprt) to monitor and possibly define women with early stage breast cancer who might be at high risk for developing secondary acute nonlymphocytic leukemia. Drs. Weaver and other VCC scientists are drafting a concept that will explore the role of erbB-2 associated signaling proteins as mediators of apoptosis for women with early stage breast cancer treated with anthracyclines (CALGB 8541). We anticipate a major increase in accrual in the next year. The Green Mountain Oncology Group (CCOP) selected the VCC as its research base beginning in April, 1997. In one month they have entered 10 patients on CALGB protocols. Two new faculty will join the VCC this summer who have major interests in genetics and high-dose therapy; it is anticipated they will be active in CALGB activities. Also, we are developing a major outreach program and expect to add several affiliates with interest in clinical trials. In addition, we have developed a high-dose chemotherapy autologous stem cell support program and expect to become a CALGB Transplant Center by the start of the next funding period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHARACTERIZATION AND TREATMENT OF MURINE MPS VII Principal Investigator & Institution: Soper, Brian W.; Jackson Laboratory 600 Main St Bar Harbor, Me 04609 Timing: Fiscal Year 2002; Project Start 01-AUG-1989; Project End 31-DEC-2006 Summary: provided by applicant): Mucopolysaccharidosis Type VII (MPS VII) is one of ten human heritable lysosomal storage diseases (LSD's). MPS VII mice and human patients suffer cognitive dysfunction, reduced hearing and sight, skeletal defects, poor joint mobility, hepatosplenomega1y, and early death. The lysosomal enzyme, betaglucuronidase (GUSB), involved in degradation of glycosaminoglycans (GAG's) is absent in MPS VII. Enzyme replacement therapy (ERT) in the mouse model demonstrates early intervention is essential to attenuate skeletal deformities and progressive learning defects. Continuous infusions can result in anaphylactic shock. Myeloablative bone marrow transplantation (BMT) alleviates disease in visceral organs, but poorly corrects the brain. Mild myeloablation is disruptive to normal brain and skeletal development and increases morbidity in neonatal recipients. Murine MPS VII provides a model to test treatment efficacy pathology), dissemination of GUSB+ donor cells (histochemistry), levels of donor enzyme (biochemistry), and functional correction (bone density, Morris water maze, retinograms, sterility, etc.). We have shown that, in the absence of myeloablation, high-dose syngeneic BMT in neonatal MRS VII mice is therapeutic in visceral and osteoid tissues. Human patients often require allogeneic BMT due to the unavailability of a matched donor. Subsequent complications are GvHD

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and HvGD. The specific aims of this study test the hypotheses that in non-ablated MRS VII neonates: (1) immature tissues such as umbilical cord blood (UCB) or fetal liver (FL) have an engrafiment advantage compared to adult bone marrow (ABM) due to reduced immunogenicity.This will be examined by competitive repopulation of allogeneic FL and ABM after prior syngeneic titration to remove stem cell (SC) content and proliferation affects that give FL competitive advantage; (2) blockage of the T cell costimulatory pathway can lead to increased frequency and/or levels of allogeneic engraftment in non-myeloablated recipients and donor lymphocyte infusion (DLI) can amplify allografts. MPS VII recipients will receive anti-CD 154 antibody and/or CTLA4Ig fusion protein and GUSB allogeneic cells. Engrafted mice will be treated with donormatched lymphocytes to competitively expand the donor graft; (3) GUSB+ SC from the brain, ABM, or FL can expand post brain ventricle implantation, reduce lysosomal storage, and improve cognitive function. Plasticity will be examined by coculture of SC from ABM and FL with neurospheres and brain SC with marrow stroma. Differentiation capacity will be compared to directly brain implanted SC. Behavioral studies will determine long-term neurological function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHIMERISM IN CORD BLOOD TRANSPLANTATION IN MICE Principal Investigator & Institution: Weinberg, Rona S.; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 05-SEP-2000; Project End 31-AUG-2005 Summary: (Investigator's abstract) Sickle cell disease (SCD) can be cured by bone marrow transplantation (BMT); however because of the morbidity and mortality associated with the procedure, BMT has been used only as a last resort for the most severely affected patients. In order for BMT and/or gene therapy to become a realistic curative therapeutic option for most sickle cell patients, it is imperative to develop less toxic preparative regimens, increase the number of available donors, develop gene therapy/transplantation protocols in which genetically manipulated autologous cells can be used, and determine the proportion of mixed chimerism required to prevent the sequelae of SCD. Umbilical cord blood (CB) has been used as an alternative source of stem cells for BMT and may provide a unique source of stem cells for gene therapy because of its easy and safe availability from individuals prenatally diagnosed with genetic disorders such as SCD. The goal is to provide effective, safe, and minimally toxic BMT and/or gene therapy for SCD patients. The hypothesis to be tested is: CB transplantation can provide stable mixed chimerism in non-ablated or minimally ablated recipients. The specific aims are to utilize a near-term fetal/newborn mouse blood (FNPB) model of CB transplantation which we and others have developed to: 1) determine the minimum number of FNPB cells which can provide long-term full engraftment or mixed chimerism in non-ablated and minimally ablated recipients; 2) transplant transgenic mice that are models of human SCD with normal FNPB stem/progenitor cells (S/PC) and to determine the proportion of donor:recipient chimerism required to ameliorate or "cure" sickle cell sequelae in these recipients; 3) use retroviral vectors containing human gamma- and beta-globin genes to transduce FNPB S/PC capable of long term engraftment and to transplant these transduced cells into non-ablated and/or minimally ablated normal and sickle cell mice. These studies are designed to define the characteristics of FNPB S/PC with regard to frequency, stem cell cycle kinetics, "stemness," and gene transducibility. BMT, including competitive repopulation assay, short-term and long-term liquid cultures, and methylcellulose cultures will be employed. These "pre-translational" studies form the basis for

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developing effective human CB transplantation and autologous CB gene therapy protocols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL APPLICATIONS OF A NOVEL FANCONI ANEMIA ASSAY Principal Investigator & Institution: Shimamura, Akiko; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 05-JUL-2002; Project End 31-MAY-2007 Summary: Congenital bone marrow failure syndromes are characterized by abnormal hematopoietic cell growth, differentiation, and survival. Bone marrow transplant is the only available curative treatment, but is associated with significant side effects and limited by donor availability. The development of new therapeutic modalities calls for investigators with: 1. Expertise in bone marrow failure syndromes, 2. An understanding of the clinical implications of new molecular discoveries, 3. Experience in the design and implementation of clinical trials. Dr. Shimamura is a pediatric hematologist/oncologist with a molecular background in signal transduction and apoptosis. The proposed training program is designed to allow her to develop expertise in bone marrow failure syndromes and to gain experience in the design and implementation of patient-oriented research. Her long-term goal is to become an independent investigatory applying our understanding of molecular mechanisms of bone marrow failure to solve clinical problems. Dr. Shimamura will pursue her career development under the co- mentorship of Dr. Alan D'Andrea and Dr. David Nathan. Dr. D'Andrea's studies have uncovered a novel Fanconi anemia (FA) biochemical pathway. She proposes to study the clinical applications of these findings as follows: 1. Investigate the FANCD activation assay as a new functional screen for the FA pathway, 2. Screen for pharmacological agents that augment FANCD activation, and 3. Assess the effect of FA gene replacement therapy on the restoration of FANCD activity as part of the on-going Dana-Farber/Children's Hospital FA gene therapy project directed by Dr. Nathan. Dr. Shimamura has assembled a committee of expert advisors and collaborators to assist her in this project. Her project will be supported by several local core facilities and programs including the Fanconi Anemia Center, the Harvard Vector Laboratory, the Cell Manipulation and Gene Transfer Laboratories, the Clinical Gene Therapy Program, and the General Clinical Research Center at Children's Hospital. To complete her training, she will attend a bone marrow failure clinic at Children's Hospital, build a bone marrow failure repository for future independent studies, and complete course work on clinical research design, implementation and analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CLINICAL RESEARCH IN STEM CELL TRANSPLANTATION Principal Investigator & Institution: Bearman, Scott I.; Cancer Center; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 14-SEP-2000; Project End 31-AUG-2005 Summary: The ongoing work and the proposed studies described in this application have, as a common theme, the use of immunotherapy as an adjunct to high-dose chemotherapy for patients with advanced or high-risk primary breast cancer. Three feasibility studies are described which form the basis for the proposed clinical trials, two of which are phase II and one of which is a randomized study. A retrospective analysis performed by Dr. Bearman's fellow, Dr. Yago Nieto, has resulted in the development of

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a model to predict patients with high-risk primary breast cancer who are at high-risk of relapse after autologous transplant. That model will identify candidates for two of the proposed clinical trials. This application also describes how Dr. Bearman will trainee young investigators in patient-oriented research. The UCHSC Bone Marrow Transplant Program has sufficient patients to conduct these studies, actively conducts both laboratory and clinical research, and is funded by both peer-reviewed and pharmaceutical support. Dr. Bearman will devote 50 percent effort to this 5 year program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE CLINICAL CENTER APPLICATION FOR DUKE UNIVERSITY ME* Principal Investigator & Institution: Kurtzberg, Joanne K.; Professor; Pediatrics; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: This project is part of a Blood and Marrow Transplant Clinical Research Network which is conducting multicenter clinical trials in hematopoietic stem cell transplantation. The purpose of the network is to promote the efficient comparison of novel treatment methods and management strategies of potential benefit for children and adults undergoing blood or marrow transplantation. Studies under development include a comparison of blood versus marrow stem cell transplantation. Studies under development include a comparison of blood versus marrow stem cell transplantation after marrow ablation, the development of non-myeloablative transplant regimens, and the best ways to avoid infections in transplant patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--FLOW CYTOMETRY Principal Investigator & Institution: Griffin, James D.; Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Goal: The goal of this unique core will be to provide cost-effective high speed flow cytometry and related services to the Program Project members. Two major uses are anticipated: 1) rapid purification of high numbers of cells transfected with a fluorescent protein, typically for experiments involving multiple samples. The purified cells need to be >95% pure and will be used for biochemical, immunological, or short term cell culture assays. 2) rapid purification of murine hematopoietic stem cells and progenitor cells for subsequent infection with retroviruses containing an oncogene or signaling molecule. These cells are typically present in low numbers, and final purity needs to be 95-99%. They will be used either for in vitro cell culture assays (such as colony assays) or for re-injection in mice as part of a bone marrow transplant experiment. Sterile sorting is essential for both types of experiments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORRECTING DYSREGULATED PERIPHERAL TOLERANCE IN NOD MICE Principal Investigator & Institution: Gill, Ronald G.; Professor; None; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2005

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Summary: (provided by applicant): Beyond the expression of autoimmune diabetes, NOD mice appear to harbor inherent defects in peripheral tolerance that renders these animals refractory to the induction of allograft tolerance. Combined, these issues make successful islet allotransplantation extraordinarily difficult in this model. Importantly, much of the autoimmune propensity in NOD mice maps to the bone marrow compartment. Depending on the donor, bone marrow transplantation can transfer either disease susceptibility or protection. In most previous studies involving tissue/organ transplantation, bone marrow has been used as a tolerogen for a specific donor and has been successfully applied in the NOD mouse. However, while conceptually very important, the toxic induction therapies involved and subsequent risk of graft-versus-host disease associated with MHC-mismatched bone marrow engraftment may preclude this approach for clinical application in the near future. In this proposal, rather than using bone marrow as a donor islet transplant-specific tolerogen, MHC-matched (H-2g7), disease-resistant bone marrow allografts will be used as a means of 're-programming' the NOD peripheral immune system to make the host amenable for tolerance induction. Thus, this proposal will test the general working hypothesis: MHC-matched, disease-resistant hematopoietic cells will dominantly regulate disease-prone cells and restore normal peripheral tolerance propensity. This hypothesis will be tested by the following specific aims: (1) Determine the extent of disease protection afforded by introducing MHC-matched, disease-resistant bone marrow in NOD mice, (2) Determine whether mixed chimerism with disease-resistant marrow will correct the inherent allograft tolerance defect in NOD mice, and (2) Determine the components within protective marrow that confer restoration of peripheral tolerance propensity in NOD mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COSTIMULATION, CHIMERISM, AND TOLERANCE Principal Investigator & Institution: Larsen, Christian P.; Professor of Surgery Transplant Center; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-MAY-2007 Description (provided by applicant): Transplantation has emerged as the preferred method of treatment for many forms of end-stage organ failure. While the short-term results have improved long-term outcomes remain inadequate. To maintain their allografts, patients must rigidly adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase the risks of cardiovascular disease, infections and malignancies. The development of strategies to promote the acceptance of allogeneic tissues without the need for chromic immunosupression could not only reduce the risk of these lifethreatening complications, but also greatly expand the application of organ, tissue and cellular transplantation for diseases such as the hemoglobinopathies and genetic immunodeficiencies, Type I diabetes, and possibly other autoimmune diseases. We have developed novel nonmyelosuppressive protocols using axiti-CD40L and CTLA4-Ig to permit the induction of titratable levels hematopoietic chimerism and robust deletional donor-specific tolerance in rodents. The goal of this project is to develop and optimize protocols to induce stable macrochimerism and transplantation tolerance to renal allografts in non-human primates. Specifically, in this proposal we will test the effects recipient conditioning with non or minimally myelosuppressive doses of busulfan or total body irradiation on the level and durability of hematopoietic chimerism when used in conjunction with a regimen consisting of anti-CD40L, CTLA-Ig, sirolimus and donor bone marrow, 2) determine whether escalating doses of G-CSF mobilized CD34+ cells will a) increase the

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level of hematopoietic chimerism, b) decrease the requirement for recipient conditioning, and c) induce transplantation tolerance to renal allografts in MHCdisparate Rhesus macaques and 3) determine the effects of an optimized tolerance induction protocol on the survival of concurrently placed renal allografts, anti-donor immune responses and protective memory T cell responses in MHC-disparate Rhesus macaques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CTLA-4 BLOCKADE TO STIMULATE ALLOGENEIC GRAFT VS TUMOR Principal Investigator & Institution: Ball, Edward D.; Professor and Chief; Cancer Center; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: This project is part of a Blood and Marrow Transplant Clinical Research Network which is conducting multicenter clinical trials in hematopoietic stem cell transplantation. The purpose of the network is to promote the efficient comparison of novel treatment methods and management strategies of potential benefit for children and adults undergoing blood or marrow transplantation. Studies under development include a comparison of blood versus marrow stem cell transplantation. Studies under development include a comparison of blood versus marrow stem cell transplantation after marrow ablation, the development of non-myeloablative transplant regimens, and the best ways to avoid infections in transplant patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CYTOKINE GENE THERAPY OF RESIDUAL LEUKEMIA Principal Investigator & Institution: Gautam, Subhash C.; Senior Staff Investigator; Internal Medicine; Case Western Reserve Univ-Henry Ford Hsc Research Administraion Cfp-046 Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Applicant's Abstract) Our long-term goal is to develop novel biotherapies that will specifically target and destroy residual leukemia. The proposed studies will test the general hypothesis that site-directed gene therapy with hematopoietic progenitor cells, genetically modified to secrete human tumor necrosis factor-alpha (hTNF-a), will significantly increase the destruction of leukemia cells remaining after high-dose chemotherapy/bone marrow (BM) transplantation. Our preliminary data show that administration of hTNF-a secreting progenitor cells following chemotherapy with cyclophosphamide (CY) and BM transplantation dramatically enhances survival (80 percent) of mice inoculated with a lethal dose of 32Dp210 murine myeloid leukemia cells without toxic side effects. We will test the hypothesis that combined therapy with CY, BM-transplant, and TNF-a secreting progenitor cells generates a greater antileukemic effect than is produced by any modality alone. We will accomplish this by the following specific aims: 1) determine the extent to which immunomodulatory effects of CY on T-helper (Th) cells and cytotoxic effector cells (CTLs and NK cells) contribute toward the antileukemic activity of CY/TNF-a gene therapy, 2) identify the cell population(s) within BM-transplant (e.g., T cells, mesenchymal cells or progenitor cells) that enhances the efficacy of combined therapy, and 3) determine whether the mechanism(s) of the antileukemic effect of CY/TNF-a treatment involves: a) augmentation of leukemia antigen presentation by dendritic cells, b) generation of

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leukemia specific (CTLs) and non-specific (NK cells/macrophages) cytotoxic effector cells, c) production of secondary cytokines with antileukemic activity, and d) the induction of programmed cell death (apoptosis) in leukemia cells. The results of these studies will demonstrate the value of combining this novel approach of site-directed TNFa gene therapy with other commonly used anticancer treatment strategies to achieve maximum destruction of residual leukemia. This would make possible the rapid implementation of this novel treatment strategy to eradicate residual leukemia in humans, without the toxic side effects of systemic TNF-a therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEFINING HEMATOPOIETIC PROGENITORS IN MOUSE BONE MARROW Principal Investigator & Institution: Spangrude, Gerald J.; Associate Professor; Oncological Sciences; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: The early progenitors of the lymphoid lineages in the mouse are not yet clearly defined. New studies regarding the nature of lymphoid progenitors have suggested that an intermediate progenitor with potential to differentiate only into T and B lineages (common lymphoid progenitor, CLP) can be isolated from adult mouse bone marrow. Other studies have demonstrated progenitors with restricted lympho-myeloid potential in fetal development, but have failed to confirm the existence of CLP. A newly developed selection protocol that completely separates hematopoietic stem cells from early progenitor cells will be utilized to investigate the characteristics of early progenitors for the lymphoid lineages in adult mouse bone marrow. In Specific Aim 1, the early stages of B cell development will be investigated to determine the identity, growth requirements, developmental potential, and genes expressed by cells defined as B cell progenitors by the new selection protocol. In Specific Aim 2, an in vivo assay for T cell development will be utilized to isolate and characterize bone marrow progenitors able to localize to and proliferate within the thymus. In Specific Aim 3, we will test the hypothesis that fate determination of CLP can be regulated by extrinsic cytokine stimulation. We propose that cells normally destined to differentiate as B lymphocytes can be redirected to T cell differentiation in short-term in vitro cultures, and that this redirection of T cell progenitor activity can account for previous discrepancies in defining lymphoid progenitors. The studies outlined in this proposal will define the early stages in the process of lymphoid lineage commitment in mouse hematopoiesis, providing a framework within which future studies aimed at mechanistic analysis of this process can be initiated. In addition, the feasibility of utilizing progenitor populations as a means to replenish the lymphoid lineages through transplantation will be evaluated. Collectively, the proposed experiments will contribute to both basic and clinical research efforts aimed at understanding the nature of early lymphoid lineage commitment in hematopoiesis and the potential of hematopoietic progenitor cells to be utilized in clinical transplant settings. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EBV GENOME EXPRESSION--LOCALIZATION OF SPECIFIC FUNCTION Principal Investigator & Institution: Hayward, S D.; Professor; Pharmacology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 30-SEP-1981; Project End 31-MAR-2005

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Summary: Epstein-Barr virus (EBV) immortalizes B cells and is associated with human malignancies including Burkitt's lymphoma, nasopharyngeal carcinoma, gastric carcinoma, Hodgkin's disease and lymphoproliferative disease in immunosuppressed patients such as AIDS patients and organ and bone marrow transplant patients. Primary infection by EBV may cause infectious mononucleosis in young adults. Primary infection leads to a proliferative expansion of the infected B cells. This is followed by the establishment of life-long persistence in which the EBV genome resides in resting B cells. Lytic viral replication occurs in the oropharynx and results in virus shedding into the saliva. Different patterns of EBV latency gene expression are seen in latently infected resting B cells and in EBV associated tumors. This application addresses factors that may regulate these expression patterns and contribute to the different aspects of EBV pathogenesis. EBV replication is necessary for virus spread and Zta is a key regulator of the EBV lytic cycle. Zta not only regulates EBV lytic DNA replication but may also influence the maintainance of latent infection. The Specific Aims are: (Aim 1). To characterize the role of Zta in replication of the EBV origin of lytic replication, orilyt. Transfection assays will be used to analyse the role of Zta in the formation of replication compartments, to analyze the relative contributions of Zta's transcriptional and replication activities to orilyt activation and to relate Zta mediated regulation of the cell cycle to Zta replication function. (Aim 2). To evaluate the contribution of the JAK-STAT signaling pathway to the regulation of EBV latency gene expression in in vivo latency and tumorigenesis. STAT regulation of individual EBV latency promoters will be examined in transient assays. The role of activated STATs and Zta expression in the maintainance of EBV positive epithelial tumor cell lines in culture will be pursued and negative regulation of the EBV lytic cycle by STATs will be examined. (Aim 3). A role for EBNA-1 in the regulation of EBV latency gene expression will be evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENTERAL TRANSPLANT

NUTRITION

&

SAFETY

IN

BONE

MARROW

Principal Investigator & Institution: Malone, Frances R.; Physiological Nursing; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-MAY-2004 Summary: (provided by applicant): Bone marrow transplant has now been expanded to include other sources of stem cells, thus the emergence of the use of the term hematopoietic stem cell transplant, as it includes stem cells from sources other than the bone marrow. Cytotoxic myeloablative therapy (chemotherapy and radiation intended to destroy bone marrow and to make room for new cells through a transplant) destroys the mucosa of the intestinal tract, impairing functions of the epithelium that are essential to health. Enteral nutrition (taking nutrients from food via the intestinal tract) is essential for the mucosa to adequately absorb nutrients from food. Enteral nutrition promotes the structural integrity of the gut. The provision of enteral nutrition during chemotherapy has protective effects on the gut, and the provision of early enteral feedings has a beneficial effect on complication and sepsis rates after surgery. Since hematopoietic cell transplant recipients experience many of the factors that facilitate movement of bacteria into the bloodstream, invasion by enteric microorganisms might commonly occur in this population. Therefore, early enteral feeding to restore the mucosa can be expected to decrease bacterial translocation and its consequences. The specific aims of the study are to investigate the safety and feasibility of early enteral feeding in pediatric cell transplant patients. Secondary and long term goals of this study are to (1) describe the clinical impact of early luminal feedings on oral intake, (2)

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describe the physiologic impact of early luminal feedings on cytokine production, and (3) describe the physiologic impact of early luminal feedings on bacterial translocation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVOLUTION OF HIV-1 IN GENETICALLY HUMANIZED MOUSE MODELS Principal Investigator & Institution: Su, Lishan; Associate Professor; Microbiology and Immunology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): This project extends our long-standing interests in establishing a murine model to study HEV replication, pathogenesis and therapy. HIV-1 is unable to infect murine cells. Attempts to "genetically humanize" the mouse with HIV-1 receptors have yielded only limited success. HIV-1 can establish initial infection in vitro or in vivo in cells or transgenic mice expressing human CD4, CCR5 (or CXCR4), and the Tat cofactor cyclin TI, but with no sustained replication and spread. Therefore, additional human factors, and possible murine factors that inhibit HIV-1 replication, will make further humanization of the mouse for H N replication difficult. However, a highly mutable virus like HIV-1 will be able to adapt to replicate in such Genetically Humanized Mouse (GHM) cells. I propose to make HN-1 "do the work" to evolve in GHM cells both in vitro and in vivo. The putative HIV-1 variants will depend on human CD4lCCRS and Tat/cyclin TI to infect the GHM cell. The specific aims are: 1. To adapt HIV-1 to replicate in GHM cells with GHM/human cell co-cultures in vitro and in vivo. The GHM mouse has overcome three blocks for HIV-1 infection. The failure of HIV-1 to replicate efficiently in the GHM cell, either due to a lack of additional human factors or presence of negative murine factors, provides a genetic selection system for HIV-I to "evolve" in these cells. As successfully demonstrated with murine hepatitis virus (MHV), it is possible to direct host (species)-range shift by using escalating ratios of restrictive/permissive target cells. I will start a similar evolution process with CXCR4tropic, CCR5-tropic and CXCR4/CCRS dual-tropic HIV-1 isolates in vitro in GHM and human cells. In addition, I will use GHM bone marrow (BM) cells to reconstitute SCIDhu ThyLiv mice which have been infected/depleted with HIV- 1. This allows HIV-1 adaptation from human cells to GHM cells in vivo at an increasing GHM/human cell ratio. Murine T cells developed in the HIV-1 infected ThyLiv organs will be activated in vitro to expand and recover the HIV- 1 variants. 2. To derive HIV-1 variants evolved to replicate in the GHM mouse in vivo. I will use two different approaches. First, I will inoculate HIV-1 (evolved from aim 1 or infected human cells) in the thymus of newborn GHM mice, whose immune system is actively developing (but immature) and should be permissive to viral infection. Second, I will infect the GHM BM cells (containing T, macrophage and progenitor cells) with. the evolved WN-1 (or infected human cells) and reconstitute lethally irradiated GHM mice with the HIV-infected BM cells. The HIV infection and bone marrow transplant procedure will be repeated to expand the NIV- 1 variants. A murine model for studying HIV-1 pathogenesis and host immune responses will be obviously invaluable for studying HIV-1 replication, pathogenesis and therapy. The adapted HIV-1 will infect the GHM model via human CD4 and coreceptors, and human cyclin T1. It is likely that the adapted HIV in the GHM model will lead to AIDSlike diseases because 1) human CD4 is essential for CD4 T development and function in the GI-IM mouse; 2) both CD4 T and macrophage cells are HIV targets; and 3) expression of nef in transgenic mouse models can lead to AIDS like diseases. Even if no AIDS-like pathology were developed, the GHwf model infected with the HIV-1 variants

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will be still useful for testing therapeutics that target HIV- 1 entry, tat- mediated gene expression and neutralizing antibody response in this model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXTRACELLULAR MATRIX IN RENAL FIBROSIS Principal Investigator & Institution: Fogo, Agnes B.; Professor; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-APR-1992; Project End 31-MAR-2007 Summary: Description (provided by applicant) Transforming growth factor-beta 1 (TGFbeta) has been implicated as a key molecule in fibrosis, and its expression is increased in numerous fibrotic conditions. The relationship of TGFbeta to other profibrotic mechanisms, such as angiotensin and plasminogen activator inhibitor-1 (PAI-1), and the differential role of infiltrating versus parenchymal cells are complex. TGFbeta can be locally activated by alphavbeta6, which is an integrin heterodimer that is expressed in epithelia in lung, skin and kidney and mediates cleavage of TGFbeta from latency associated peptide. Mice deficient in avB6 lack the ability to activate local TGFbeta through this alphavbeta6 integrin dependent mechanism and had marked protection against fibrosis in the unilateral ureteral obstruction model, with decreased PAI-1 expression, despite robust infiltration of macrophages. A full fibrotic response was restored by infusion of angiotensin or aldosterone, together with restoration of local increase of PAI-1. These projects will examine the TGFbeta1 dependent and independent mechanisms of fibrosis. We hypothesize that PAI-1 induction occurs even in the absence of local TGFbeta, and that PAI-1 by itself can effect fibrosis. We further hypothesize that both parenchymal and infiltrating cell mechanisms are necessary for full fibrotic response. We postulate that injury promotes epithelial-mesenchymal transdifferentiation, and that inadequate macrophage clearance of apoptotic cells both contribute to fibrosis. We will use the alphavbeta6 knockout mouse and bone marrow transplant, to experimentally manipulate parenchymal versus infiltrating cells combined with pharmacological manipulations, to determine mechanisms of interstitial fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUNCTION OF CD34 STEM/PROGENITOR CELLS Principal Investigator & Institution: Sharkis, Saul J.; Professor; Oncology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2004 Summary: Hematopoietic stem cells are a rare population of cells which have a unique biological profile. This population can be used for cellular therapy of hematological malignancy, bone marrow failure disorders, as well as gene therapy. for more than a decade the CD34 antigen has been used to help isolate this rare population in humans. Transplantation of CD34 positive cells in patients has resulted in prompt engraftment of donor cells. Recently, through the development of antibodies to the CD34 antigen on mouse tissues, it has become possible to study the stem cell biology (i.e., proliferation, differentiation, survival, and self- renewal) using a transplant strategy to determine the importance of CD34 in identifying stem cells. Most stem cell biologists will agree that the stem cell pool is heterogenous with the earliest (highest quality) stem cell having potentials for proliferation, differentiation, survival, and self-renewal but as the stem cell matures these potentials are lost. It becomes critically important in diseases with stem cell intrinsic defects to use the highest quality stem cell for cellular therapy.

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Recently, conflicting reports have appeared which have made it more difficult to assess functional significance of the CD34 antigen. Our first specific aim will examine the role of CD34 for self-renewal, proliferation, and differentiation. This will involve transplantation of CD34 null stem cells into normal mice and normal cells into null mice to test the competence of these cells in a transplantation protocol. We will also examine the recovery of endogenous stem cells to either radiation or 5-fluorouracil exposure to assess the endogenous competence of CD34 null stem cells. Specific aim 2 will study the compensatory mechanisms that may be at play in allowing CD34 null mice to survive to adulthood with mildly affected hematopoietic phenotypes. Finally, we will study the homing potential of stem cells from CD34 null mice to engraft normal recipients using a recently developed homing assay in which we will tag stem cells in vivo. We expect that the results of our studies will be directly applicable to treatment of hematological disorders, genetic diseases, and malignancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RECEPTORS

FUNCTIONAL

HIERARCHY

OF

REMNANT

LIPOPROTEIN

Principal Investigator & Institution: Fazio, Sergio; Associate Professor; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: (Adapted from applicant's abstract): The focus of this grant is the elucidation of the mechanism by which remnant lipoprotein particles are cleared by hepatic receptors. The Principal Investigator and his colleague, Dr. M. Linton, have pioneered the use of bone marrow transplant to study apo E delivery into genetically altered mice via transplanted macrophages. The critical observation in the preliminary data, which serves as the basis for the grant proposal, is that BMT into apo E deficient mice is capable of fully restoring normal lipid levels, but the same transplantation does not normalize lipids in animals that are deficient in both apo E and the LDL receptor. Apo E deficient animals who are homozygous for the LDL-R have a good response to BMT, but lipid values are higher than in animals with two intact genes encoding the LDL-R. Importantly, the apo E levels in the double ko animals are even higher than those found in normal mice, and data presented in the grant indicates that this apo E is present in the space of Disse in the liver, where lipoprotein capture by hepatic lipoprotein receptors should occur. These findings indicate that the apo E provided by macrophages does not substitute fully for endogenous hepatic apo E in generating a pathway that can metabolize remnant particles. The PI lists three major specific aims, each of which is divided into three subaims. The first aim is designed to assess the roles of the LDL receptor and the LRP receptor in the clearance of remnant lipoproteins using bone marrow transplantation of apo E expressing macrophages to partially re-constitute apo E expression in mice genetically deficient in apo E and the LDL-R. Turnover studies of apo B-48 and apo B-100 remnants will be analyzed before and after transplantation and the fate of lipoprotein associated apo E after internalization by either the LRP or LDL-R will be studied. In Specific Aim 2, the investigators will test their hypothesis that secretion-capture of lipoproteins in the space of Disse is critical to remnant uptake and that this process requires local apo E production by the hepatocyte. This will be accomplished using an adenovirus to express E locally in E deficient animals, before and after BMT. The effect of apo E expression on LRP activity will be assessed by radiolabeled antibodies directed against LRP in vivo, complemented by in vitro studies of apo E enriched B-VLDL binding to fibroblasts deficient in either the LDL-R or the LRP. The third specific aim will focus on the role of apo E and LRP in macrophage foam

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cell formation and atherosclerosis. BMT into LDL-R /apo E double ko's will permit the assessment of macrophage-specific E expression on atherosclerosis development in animals with persistently elevated lipids. Fetal hepatocyte transplantation is proposed as a method for generating LRP deficient macrophages to determine what activities of wild type macrophages are attributable to LRP. Finally, in vitro studies will be conducted to assess the role of LRP in the binding and degradation of B-VLDL. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC MANIPULATION OF T CELLS--PRECLINICAL MODELS Principal Investigator & Institution: Dipersio, John F.; Cheif, Division of Oncology; Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Applicant's Description Verbatim): Allogeneic bone marrow transplantation is a curative therapy for hematologic malignancies, marrow failure states, and selected inherited metabolic diseases. Unfortunately, BMT is associated with significant morbidity and mortality related to graft vs. host disease (GvHD). Attempts to mitigate GvHD using T-cell depletion resulted in increased rates of graft failure, post-transplant lymphoproliferative diseases, leukemia relapse and opportunistic infections. We propose to genetically modify T-cells using novel cell surface chimeric suicide genes. We will test the expression and purification of novel fusion suicide genes in vitro and in vivo using instructive transgenic and "knock-in" murine pre-clinical models. The optimal method and potential role of genetically manipulated T-cells to mitigate GvHD while maintaining engraftment and graft vs. leukemia can only be defined by developing new reagents and novel pre-clinical murine transplant models. We propose to generate important new reagents to study T-cell transduction by suicide genes and to use a number of well-defined pre-clinical models to develop a rational approach and a clear foundation for future clinical trials. In Aim I, we will design methods to optimize transduction, selection, and expansion of transduced T-cells, using OKT3 and 11-3 and CD3/CD28 magnetic beads. In addition, we will generate novel second-generation suicide genes designed to optimize detection and killing in response to prodrug. We will also test the survival and function of transduced murine and human T cells using in vivo using allogeneic transplant models and several murine SCID models. Aims II and III, we will use the chimeric suicide genes developed in Aim I to generate informative transgenic and knock-in pre-clinical murine models in which these suicide genes will be expressed in all (Aim II) or in subsets (Aim III) of peripheral T-cells. Allogeneic bone marrow transplantation will be performed using the transgenic and knock-in mice developed in Aims II and III to further develop the optimal method of suicide in vivo, its effect on GvHD and engraftment, and its possible role in clinical trials. In Aim 1V, we will utilize three novel murine leukemia models in which the effects of genetically modified T-cells and their in vivo suicide on GvHD, engraftment and graft vs. leukemia can be compared to animals receiving unmanipulated T-cells and T-cell depleted BM. These studies will provide new insights into the pathophysiology of GvHD and its effective treatment. Issues regarding the use of genetically manipulated T-cells to control GvHD can best be investigated through the use of informative animal models and the comprehensive studies described in this proposal. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HEMATOPOIETIC CELL TRANSPLANTATION FOR MALIGNANCY Principal Investigator & Institution: Forman, Stephen J.; Director; City of Hope National Medical Center Duarte, Ca 91010

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Timing: Fiscal Year 2002; Project Start 01-JUL-1981; Project End 31-MAR-2003 Summary: This Program Project Grant application seeks support for clinical and experimental studies concerning the major obstacles to successful allogeneic and autologous stem cell transplantation for the treatment of hematologic malignancies. These problems include recurrence of the underlying disease, graft-versus-host disease and infectious with cytomegalovirus. The program consists of two clinical and four experimental projects that are supported by six cores. The two clinical projects propose studies designed to eradicate leukemia and lymphoma utilization innovations in the preparatory regimen as well as in the treatment of minimal residual disease following either allogeneic and lymphoma antigens in the preparatory regimen of patients undergoing allogeneic for leukemia and myelodysplasia or autologous transplantation for lymphoma. It is also the goal of our studies to use antigen-specific cytolytic T cells in the treatment of minimal residual disease in patients undergoing autologous transplantation for B cell lymphoma and allogeneic transport for Ph+ ALL. Two transplant studies involve genetic manipulation of hematopoietic cells to convey resistance to HIV in patients with HIV-related lymphoma utilizing adeno-associated virus and lentiviruses. Studies will also continue on the prevention of graft-versus- host disease and will develop novel immunologic strategies to prevent cytomegalovirus disease after allogeneic transplantation. The two clinical projects in allogeneic and autologous transplantation serve as a resource for the experimental projects in the program. The four experimental projects address biologically important questions related to transplantation including acquisition of immunity to CMV, the development of antigen-specific cytolytic T cells, treatment of minimal residual disease after autologous and allogeneic transplantation, and genetic modification of stem cells to induce HIV resistant immune reconstitution. These projects attempt to bring laboratory based innovative concepts to clinical use in the treatment of Administration for the coordination of research, Biostatistics, Cellular and Molecular Correlative studies, radioimmunotherapy, Long-Term Follow-Up and a new Biomedicine Production Facility for the production of antibodies, antigen specific cells and viral vectors to be used in the experimental studies proposed in this grant. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEMATOPOIETIC PROGENITOR CELLS Principal Investigator & Institution: Shpall, Elizabeth J.; Associate Director; Blood & Marrow Transplantation; University of Texas Md Anderson Can Ctr Cancer Center Houston, Tx 77030 Timing: Fiscal Year 2003; Project Start 17-SEP-1993; Project End 31-MAR-2008 Summary: (provided by applicant): Umbilical cord blood (CB) is used to restore hematopoiesis in bone marrow transplant patients lacking sibling or unrelated donors. A major disadvantage of CB is the low cell dose with resultant delays in neutrophil engraftment and a high rate of engraftment failure. The major hypothesis of this grant is that CB progenitors expanded ex vivo prior to transplantation will provide more rapid neutrophil engraftment and less engraftment failure than unmanipulated CB. There are two populations that have been proposed to be responsible for rapid myeloid recovery: 1) mature progenitor cells, and 2) primitive hematopoietic stem cells. In this grant we will conduct three sequential phase II clinical trials to evaluate CB grafts expanded ex vivo to generate mature progenitors or primitive stem cells. The first trial, a continuation of the previous R01, will evaluate CB grafts in which committed CD34+ precursors have been selectively expanded. The second trial will evaluate CB grafts in which more primitive CB cells are expanded, using earlier-acting growth factors and novel

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technology described in the grant. Based upon the findings of these studies, the third trial will randomize patients to receive CB progenitors which are unmanipulated vs. expanded, using the expansion methodology in the first two trials that results in the fastest engraftment. We anticipate that infectious complications will be a major cause of morbidity and mortality in these trials. Although expanded CB may hasten neutrophil engraftment and reduce infections early posttransplant, it may not affect infections associated with delayed immune recovery. Delays in immune reconstitution in CB recipients are frequently reported. It is possible that the CB purification and expansion methods proposed in this grant, which result in selective loss of lymphoid cells, could further compromise immune reconstitution. Thus, we plan to comprehensively evaluate the immune reconstitution of CB recipients enrolled on the proposed trials. General immune function and CMV-specific immune reconstitution will be studied, because of the multiple, complimentary assays available and the expertise of the co-investigators who will be performing them. By randomizing patients in the third trial, we will be able to make an estimate of the relative efficacy of CB expansion technology as well as immune reconstitution in recipients of unmanipulated vs. expanded CB. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEMATOPOIETIC TRANSFORMATION BY TYROSINE KINASE FUSIONS Principal Investigator & Institution: Gilliland, D Gary.; Associate Professor; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The overall hypothesis of this proposal is that a detailed characterization of the signal transduction properties of constitutive activated tyrosine kinases associated with human leukemias will identify the critical targets that are required for transformation of hematopoietic cells. These targets can then be exploited for the development of novel therapeutic approaches to leukemia. During the previous funding period, we accomplished each of the goals that were set forward. In particular, we cloned and characterized the transforming properties of a spectrum of tyrosine kinase fusions associated with recurring chromosomal translocations in human leukemias, using both cell culture systems and murine models of leukemia. These include, in addition to the TEL/PDGFbetaR and TEL/ABL fusions, the HIP1/PDGFbetaR, H4/PDGFbetaR, TEL/JAK2 and TEL/TRKC fusion proteins. The availability of a spectrum of constitutively activated tyrosine kinases provides a unique opportunity to identify critically important pathways of transformation through comparative analysis of the signal transduction pathways and target genes activated by these fusion proteins, with validation in animal models. In Specific Aim 1, we will address the hypothesis that characterization of the signal transduction pathways and target genes activated by TEL/PDGFbetaR, TEL/JAK2, TEL/TRKC, and TEL/ABL, and BCR/ABL, will identify critical pathways and targets that are required for transformation. We will utilize standard approaches to analysis of signal transduction, as well as expression arrays. In Specific Aim 2, we will test the hypothesis that the putative critical effectors of transformation identified in Specific Aim 1 can be evaluated and validated in our model systems. We will utilize a combination of approaches that focus on inhibition of transformation in cell culture systems, as well as murine bone marrow transplant models of leukemia using hematopoietic progenitors from donor mice are that are genetically deficient in one or more of the putative targets. In Specific Aim 3, we will test the hypothesis that acute leukemia phenotypes are a collaboration between constitutively activated tyrosine kinases and transcription factor fusion genes

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such as AML1/ETO, AML1/EVI1 and NUP98/HOXA9. We hypothesize that coexpression of tyrosine kinase fusions and transcription factor fusions will cause an acute leukemia phenotype in murine models, and that these leukemias will retain sensitivity to specific tyrosine kinase inhibitors. This proposal will provide insights into signal transduction and target genes critical for transformation of hematopoietic cells, as well as novel therapies for leukemia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEMOSTASIS CLINICAL RESEARCH NETWORK PROTOCOLS Principal Investigator & Institution: Leissinger, Cindy A.; Medicine; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Patients with disorders of hemostasis are subject to long term problems and risks, difficult treatment decisions and risks associated with treatment itself. Many of these risks and complications can be lessened or prevented by appropriate intervention strategies. Advances in the management of patients with bleeding disorders of relatively low incidence require: 1) that clinical studies utilize a multi-institutional cooperative network in order to accrue sufficient numbers of patients to achieve meaningful answers; and 2) that patients be educated on the vital importance of participation in such studies. The purpose of this project is to develop a Hemostasis Core Clinical Research Unit at Tulane University as part of the NIH Transfusion Medicine/Hemostasis Clinical Research Network. This Unit will be developed using some of the basic infrastructure and services of the Tulane Center for Bleeding Disorders, which is dedicated to the care and advancement of patients with disorders of hemostasis. Once established, this Core Research Unit will provide access to clinical trials for hemostasis patients from the Center for Bleeding Disorders, the Bone Marrow Transplant Unit and from throughout the network of Tulane affiliated hospitals and clinics. In addition, two clinical trial protocols have been developed as part of this proposal. The first, A prospective randomized crossover study of activated prothrombin complex concentrates (aPCCs) as prophylactic therapy in hemophilia A patients with inhibitors, is a long-term protocol designed to evaluate the efficacy of aPCCs in the prevention of bleeds in this very complicated group of patients. The second, short-term protocol, A prospective study of ribavirin for the treatment of HIVassociated immunopathic thrombocytopenic purpura (ITP), was developed to test a novel pharmacologic agent in the management of HIV-ITP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: HIGH PERFORMANCE MAGNETIC CELL SORTING Principal Investigator & Institution: Chalmers, Jeffrey J.; Professor; Chemical Engineering; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 21-JUL-2003; Project End 31-MAR-2007 Summary: (provided by the applicant): An area of increasing interest, and potentially significant clinical use, is performing mismatched stem cell transplants for high-risk and refractory hematological malignancies using related donors. Such patients currently undergo transplants using HLA matched sibling or unrelated donor stem cells. Using haplotype-mismatched donors from siblings, parents or children would permit the availability of suitable donors for more than 90-95% of candidate patients. However, the main limitation is graft-versus-host disease (GVHD). GVHD can be almost eliminated by extensive T-cell depletion (>5 logs). While T cell depletion increases the risk of graft

Studies

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rejection, this can be overcome by the use of very large doses of stem cells. Therefore, it is desirable to have a system where very large numbers of stem cells can be efficiently processed to deplete T-cells, and with minimal loss of these stem cells. A second area of increasing interest, and potentially significant clinical use, is the isolation of Natural Killer (NK) Cells for Immunotherapy. NK cells are important cells of the innate immune system that are not involved in specific antigen recognition. These cells are important in the defense against infections, but also have potent anti-tumor effects. Currently, there is growing interest in the use of both autologous and allogeneic activated NK cells for cancer immunotherapy. In particular, the use of allogeneic NK cells mismatched for HLA-C alleles of the recipient can exert very potent anti-leukemic effect in vitro. Infusion of NK cells may also assist engraftment of stem cells in the bone marrow transplant setting. This project will focus on the development/application of a high throughput, flow through immunomagnetic cell separation system currently under development for clinical scale T-cell depletion and NK isolation. While several systems have been developed, none are currently approved for these indications, and their performance is generally suboptimal. With respect to the recovery of stem cells during T-cell depletion, a significant increase in stem cell recovery is needed, from reported mean values of 41 to over 80%, to facilitate 'mega-dose' CD34 cell therapy in mismatched transplants. Less research has been carried out for clinical scale NK cell separation technology, with current methods performing sub-optimally due to loss of over 50% of the NK cells. Specifically, therefore, our objectives are: 1.To demonstrate significantly superior performance for T-cell depletion with the aim of achieving 5 log10 depletion of T cells, with >90% recovery of CD34+ cells in greater than or equal too 80% of clinical apheresis samples obtained from normal donors. 2. To demonstrate significantly superior performance of NK cell isolation with the aim of isolating CD56+ CD3- NK cells with > 90% recovery and with

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