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Chronic Graft-versus-Host Disease—Implementation of the National Institutes of Health Consensus Criteria for Clinical Trials

2008; Elsevier BV; Volume: 14; Issue: 4 Linguagem: Inglês

10.1016/j.bbmt.2008.01.005

1523-6536

Linda M. Griffith, Steven Z. Pavletic, Stephanie J. Lee, Paul J. Martin, Kirk R. Schultz, Georgia B. Vogelsang,

Immunotherapy and Immune Responses

Based on collaborative discussions of the community of hematopoietic cell transplant (HCT) physicians, the National Institutes of Health (NIH) Consensus Criteria for Clinical Trials in Chronic Graft-versus-Host Disease (GVHD) established for the first time comprehensive diagnostic, staging, and response criteria for chronic GVHD (cGVHD). The recommendations from this group were published in a series of articles in this journal [1Filipovich A.H. Weisdorf D. Pavletic S. et al.National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.Biol Blood Marrow Transplant. 2005; 11: 945-956Abstract Full Text Full Text PDF PubMed Scopus (2883) Google Scholar, 2Shulman H.M. Kleiner D. Lee S.J. et al.Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. Pathology working group report.Biol Blood Marrow Transplant. 2006; 12: 31-47Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 3Schultz K.R. Miklos D.B. Fowler D. et al.Toward biomarkers for chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: III. Biomarker working group report.Biol Blood Marrow Transplant. 2006; 12: 126-137Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 4Pavletic S.Z. Martin P. Lee S.J. et al.Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. Response criteria working group report.Biol Blood Marrow Transplant. 2006; 12: 252-266Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar, 5Couriel D. Carpenter P.A. Cutler C. et al.Ancillary therapy and supportive care of chronic graft-versus-host-disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary therapy and supportive care working group report.Biol Blood Marrow Transplant. 2006; 12: 375-396Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 6Martin P.J. Weisdorf D. Przepiorka D. et al.National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: VI. Design of clinical trials working group report.Biol Blood Marrow Transplant. 2006; 12: 491-505Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. Implementation of the criteria and follow-up research are needed to ensure continued progress. Therefore, representatives of the national and international cGVHD community met in Bethesda, MD, on March 8 and 9, 2007, to report on continuing studies, identify unmet needs, and consider future options. Here, we summarize findings of the 2-day meeting and the present spectrum of activities in the field of cGVHD. There is considerable need to evaluate the diagnosis, staging, and response criteria prospectively in clinical trials and retrospectively using existing databases. It is highly likely that refinements will be needed, because such criteria should always be considered a “work in progress,” as clinical practice and treatments evolve over time. Challenges to completion of validation studies include the large number of patients from multiple centers required for an adequate statistical evaluation, the protracted time frame needed for adequate observation, and funding needed to support the effort. Jagasia et al. [7Jagasia M. Giglia J. Chinratanalab W. et al.Incidence and outcome of chronic graft-versus-host disease using National Institutes of Health consensus criteria.Biol Blood Marrow Transplant. 2007; 13: 1207-1215Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar] and Arora et al. [8Arora M. Nagaraj S. Witte J. et al.New classification of chronic graft versus host disease: added clarity from the consensus diagnoses.Blood. 2007; 110 (Abstract #41)Google Scholar] have recently completed the first single-site retrospective validation studies of the diagnosis and staging criteria. These studies showed a correlation of GVHD subtype (late acute versus classic chronic) and severity with overall survival (OS). At the workshop, Jacobsohn et al [9Jacobsohn D.A. Chen A.R. Zahurak M. et al.Phase II study of pentostatin in patients with corticosteroid-refractory chronic graft-versus-host disease.J Clin Oncol. 2007; 25: 4255-4261Crossref PubMed Scopus (78) Google Scholar] presented a comparison of the Johns Hopkins Hospital skin response criteria as used in the recently published pentostatin trial with the NIH consensus response criteria. Their data showed that the 2 scales had similar and complementary, although not identical, properties. Mitchell et al. [10Mitchell S. Reeve B. Cowen E. et al.Feasibility and reproducibility of the new NIH consensus criteria to evaluate response in chronic GVHD—a pilot study.Blood. 2005; 106 (Abstract #3121)Google Scholar] have performed a small assessment of feasibility and reproducibility of the NIH response criteria in a prospective study conducted at multiple sites in the United States. A large prospective cohort investigation has recently received NIH funding and is led by S. Lee of the Fred Hutchinson Cancer Research Center (FHCRC). A validation project is currently underway led by D. Wolff and the German/European Union (EU) collaborative group [11Wolff D. Herzberg P.Y. Heussner P. et al.Prospective evaluation of the NIH staging criteria in chronic GVHD and correlation to quality of life—results of a German multicenter validation trial.Blood. 2007; 110 (Abstract #42)Google Scholar]. Because the multiple-organ clinical manifestations of cGVHD can persist for prolonged periods of time, supportive care is critical in long-term management. Because there is a profound lack of data in these areas, most of the NIH consensus recommendations are based on extrapolation of clinical results from other fields of medicine. To conduct trials in this area it will be essential to develop organ-specific severity scales, which will require long-term data. Research addressing organ dysfunction includes skin, pulmonary, and oral mucosal complications and conjunctival therapeutic intervention studies. The bronchiolitis obliterans syndrome (BOS) is a rare, but devastating, complication in need of improved diagnostic criteria and therapy [12Yoshihara S. Yanik G. Cooke K.R. Mineishi S. Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic cell transplantation.Biol Blood Marrow Transplant. 2007; 13: 749-759Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar]. Studies of oral mucosa suggest that immunologic features of cGVHD might be quantified by immunohistochemistry. This type of research represents an opportunity to study the immunologic processes of cGVHD directly at the anatomic site of the disease [13Imanguli M. Hakim F. Swaim W. et al.The balance of effector and regulatory cell populations in oral chronic GVHD: potential role of IL-15.Blood. 2007; 110 (Abstract #1059)Google Scholar]. Chronic GVHD is remarkable for lack of insight into the basic biology of the disease. Because of this, there are no validated biomarkers. Targeted drug therapy has been impaired by this absence of specific immunologic targets. Preclinical mouse models that approximate the full spectrum of human cGVHD are lacking, although there are several useful models that demonstrate selected aspects of the disease process (reviewed by Shlomchik et al. [14Shlomchik W.D. Lee S.J. Couriel D. Pavletic S.Z. Transplantation's greatest challenges: advances in chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2007; 13: 2-10Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar] and Chu and Gress [15Chu Y-W, Gress RE. Murine models of chronic graft-versus-host disease: insights and unresolved issues. Biol Blood Marrow Transplant. (accepted for publication).Google Scholar]). The long duration of follow-up required to assess murine cGVHD has inhibited both the development and utilization of these models. Prior studies using patient samples have focused mainly on peripheral blood, which likely misses mechanisms that function within tissues affected by cGVHD. Studies to characterize new biomarkers and confirm or refute those suggested by smaller studies in cGVHD will require large numbers of samples linked to detailed information on the clinical course. Small studies have suggested a role for diverse immunologic cells/soluble factors including T cells and T cell subsets, thymic-dependent and -independent pathways of T cell recovery, B cells, and B cell subsets, and B cell activating factor (BAFF) [16Fujii H, Cuvelier G, She K, et al. Biomarkers in newly diagnosed pediatric extensive chronic graft-versus-host disease: a report from the Children's Oncology Group. Blood. [E-pub ahead of schedule October 9, 2007, DOI 10.1182/blood-2007-08-106286].Google Scholar, 17She K. Gilman A.L. Aslanian S. et al.Altered Toll-like receptor 9 responses in circulating B cells at the onset of extensive chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2007; 13: 386-397Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 18Dickinson J.D. Pusic I. Rader C. et al.Soluble BAFF is elevated following allogeneic hematopoietic stem cell transplantation but is not an early predictor for the development of chronic GVHD.Blood. 2007; 110 (Abstract #167)Google Scholar, 19Sarantopoulos S. Stevenson K. Kim H.T. et al.High levels of B-cell activating factor in patients with active chronic graft-versus-host disease.Clin Cancer Res. 2007; 13: 6107-6114Crossref PubMed Scopus (204) Google Scholar]. For example, 4 inflammatory plasma markers and an activated B cell population identified as potential biomarkers in cGVHD in a study performed by the Children's Oncology Group (COG) will require validation in a larger population that includes adults [16Fujii H, Cuvelier G, She K, et al. Biomarkers in newly diagnosed pediatric extensive chronic graft-versus-host disease: a report from the Children's Oncology Group. Blood. [E-pub ahead of schedule October 9, 2007, DOI 10.1182/blood-2007-08-106286].Google Scholar, 17She K. Gilman A.L. Aslanian S. et al.Altered Toll-like receptor 9 responses in circulating B cells at the onset of extensive chronic graft-versus-host disease.Biol Blood Marrow Transplant. 2007; 13: 386-397Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar]. Larger cooperative studies, in particular those conducted by the EU, have included examination of gene polymorphisms in cGVHD [20Dickinson A.M. Harrold J.L. Cullup H. Haematopoietic stem cell transplantation: can our genes predict clinical outcome?.Expert Rev Mol Med. 2007; 9: 1-19Crossref PubMed Scopus (38) Google Scholar, 21Dickinson A.M. Risk assessment in haematopoietic stem cell transplantation: pre-transplant patient and donor factors: non-HLA genetics.Best Pract Res Clin Haematol. 2007; 20: 189-207Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar], and proteomics studies [22Weissinger E.M. Schiffer E. Hertenstein B. et al.Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.Blood. 2007; 109: 5511-5519Crossref PubMed Scopus (137) Google Scholar]. Growing clinical evidence suggests a major contribution of cGVHD in mediating allogeneic GVL effects. Research in this important area is lacking, and efforts to investigate the pathophysiologic basis of the GVL effect compared to the GVHD effect should be pursued. Representative presentations at the workshop addressed preclinical models and their limitations, T cell and B cell aspects of the GVL effect, and the role of hematopoietic chimerism. The possibility of a humoral component in the GVL effect, in addition to the documented T cell contribution, was discussed [23Wadia P.P. Coram M.A. Butte A.J. Miklos D.B. Allogeneic antibodies identify GVL targets CHAF1b and NuSAP1 in AML patients.Blood. 2007; 110 (Abstract #168)Google Scholar, 24Al-Ali H.K. Nehring C. Krahl R. et al.Donor CD34+ cell chimerism at day 28 and chronic graft-versus-host disease but not high-risk cytogenetics influence outcome of allogeneic hematopoietic cell transplantation following reduced intensity conditioning in patients with AML and MDS.Blood. 2006; 108 (Abstract #547)Google Scholar, 25Baron F. Maris M.B. Sandmaier B.M. et al.Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning.J Clin Oncol. 2005; 23 (1993-2003)Crossref Scopus (302) Google Scholar, 26Lee S.J. Klein J.P. Barrett A.J. et al.Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse.Blood. 2002; 100: 406-414Crossref PubMed Scopus (449) Google Scholar, 27Baskar S. Levy J.M. Bishop M.R. Rader C. A human monoclonal antibody and antigen discovery platform based on allogeneic hematopoietic stem cell transplantation and phage display.Keystone Symposia on Molecular and Cellular Biology; Antibodies as Drugs: From Basic Biology to the Clinic. 2007; (Abstract #213)Google Scholar]. The relation of cGVHD biomarkers to the GVL effect will be investigated in the COG study of GVHD prophylaxis for children receiving allogeneic HCT for acute lymphoblastic leukemia (see also #NCT00382109 at www.ClinicalTrials.gov). Regarding design of clinical trials in cGVHD in general, the selection of short-term endpoints was emphasized as key, including consideration of composite endpoints. Challenges to endpoint design include lack of validated short-term predictors (<6 months) of the more long-term outcomes (years) of the natural history of cGVHD, as well as the obvious need for validation studies of response criteria in cGVHD. The trajectory of disease progression should be given more attention when patients are enrolled in a clinical trial. For example, stabilization of disease manifestations could be considered a benefit in a patient with rapidly progressive cGVHD manifestations but not in those with improving or stable manifestations before an intervention. Biologic markers that could be used as short-term predictors of therapeutic benefit would be especially helpful for early drug development trials in cGVHD. Results from recent relatively small phase II studies suggestive of benefit from extracorporeal photopheresis (ECP) and Rituximab (humanized anti-CD20) for the treatment cGVHD were presented [28Flowers M.E.D. Van Besien K. Apperley J. et al.A randomized single-blind study of extracorporeal photopheresis with UVADEXR plus conventional therapy compared to conventional therapy alone in chronic GVHD.Blood. 2006; 108 (Abstract #758)Google Scholar, 29Cutler C. Miklos D. Kim H.T. et al.Rituximab for steroid-refractory chronic graft-versus-host disease.Blood. 2006; 108: 756-762Crossref PubMed Scopus (372) Google Scholar]. Multicenter studies of mycophenolate mofetil (MMF) and its enteric coated formulation as an adjunct to standard front line cGVHD therapy are currently underway in the United States led by P. Martin at FHCRC (see also #NCT00089141 at www.ClinicalTrials.gov) and in Europe led by G. Socie (#NCT00298324 at www.ClinicalTrials.gov), respectively. The total number of patients with cGVHD is small, so that cGVHD qualifies as a “rare disease,” even though as many as half of all patients undergoing allogeneic HSCT experience this complication. Cooperative clinical studies in cGVHD will be needed to accomplish progress in the field. There is a corresponding need to identify the type of infrastructure that will best facilitate such multicenter projects. Both national and international clinical collaborations should be strongly encouraged. In the United States, 1 or more existing networks, for example, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), may be well positioned to provide the type of infrastructure needed. In the recent “BMT CTN State of the Science Symposium” [30Ferrara J.L.M. Anasetti C. Stadtmauer E. et al.Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2007.Biol Blood Marrow Transplant. 2007; 13: 1268-1285Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar], cGVHD was identified as an area of immediate need for both intensive studies of disease mechanisms as well as therapeutic clinical trials. A proposal for a prospective multicenter clinical trial in cGVHD that would be coupled with immunologic ancillary studies is currently in development by the consortium. The Pediatric Blood and Marrow Transplant Consortium (PBMTC), which is a member of the BMT CTN, is an important resource for study of aspects of cGVHD. The database of the Center for International Blood and Marrow Transplant Research (CIBMTR), which contains information on over 240,000 HCT procedures performed worldwide, serves as a unique and perhaps insufficiently utilized resource available for retrospective analyses in HCT including cGVHD. Practical aspects of International collaborations were discussed at the workshop by representatives of the European Group for Blood and Marrow Transplantation (EBMT), the BMT CTN, and the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP). Availability of funding support for studies in cGVHD has been extremely limited. The standard NIH Research Project (R01) format may not be a good fit for applications in cGVHD that need a multicenter or interdisciplinary clinical trials design. For cGVHD in particular, the relatively small number of cases, with lack of clear assignment of responsibility to a single NIH Institute/Center (IC) presents an additional challenge in applying for and successfully obtaining NIH funding. However, even in this era of relative fiscal constraint for the NIH, using the National Institute of Allergy and Infectious Diseases (NIAID) as an example, over half of the annual budget of the Division of Allergy, Immunology and Transplantation (DAIT) remains available for investigator-initiated research, representing a significant opportunity [31Hackett C.J. Rotrosen D. Auchincloss H. Fauci A.S. Immunology research: challenges and opportunities in a time of budgetary constraint.Nat Immunol. 2007; 8: 114-117Crossref PubMed Scopus (15) Google Scholar]. It may be reasonable to consider cooperation of NIH ICs having a direct or partial interest in cGVHD studies, or support through existing networks or other consortia, when developing a funding plan for large cooperative clinical trials. A Program Project (P01) approach may be appropriate. Interactive discussions with U.S. Government funding agencies should be pursued, to promote intramural and extramural NIH and government-wide collaborations where feasible. Investigators should approach NIH ICs with their proposals for joint ventures. It is likely that the NIH would view collaborative efforts that result in elimination of redundant funding or cost saving as advantageous. Opportunities for funding other than NIH should be considered, including other U.S. Government agencies, such as, for example, the Food and Drug Administration (FDA) Office of Orphan Products Development, as well as private foundations such as the Biomarkers Consortium of the Foundation for the NIH, and others. The opinions expressed are those of the authors and do not represent the position of the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Institutes of Health, or the U.S. Government. This workshop was sponsored by the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the Office of Rare Diseases, National Institutes of Health, Bethesda, MD. Linda M. Griffith, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD; Steven Z. Pavletic, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD Barry D. Anderson, National Cancer Institute, Bethesda, MD; Joseph H. Antin, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Mukta Arora, Center for International Blood and Marrow Transplant Research (CIBMTR), University of Minnesota, Minneapolis, MN; Kristin Baird, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Paul A. Carpenter, Fred Hutchinson Cancer Research Center, Seattle, WA; Jason W. Chien, Fred Hutchinson Cancer Research Center, Seattle, WA; Daniel R. Couriel, MD Anderson Cancer Center, University of Texas, Houston, TX; Corey S. Cutler, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Anne M. Dickinson, University of Newcastle-Upon-Tyne, Newcastle-Upon-Tyne, UK; James L. M. Ferrara, University of Michigan, Ann Arbor, MI; Mary E. D. Flowers, Fred Hutchinson Cancer Research Center, Seattle, WA; Thea M. Friedman, Hackensack University Medical Center, Hackensack, NJ; Hildegard T. Greinix, Vienna Medical School, Vienna, Austria; Ronald E. Gress, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Fran Hakim, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Lee J. Helman, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD; ∗Dr. Holler and Dr. Vogelsang contributed substantially to presentations at this meeting, although they were unable to attend personally.Ernst Holler, University Hospital Regensburg, Regensburg, Germany; Matin M. Imanguli, Center for Cancer Research, National Cancer Institute, Bethesda, MD; David A. Jacobsohn, Children's Memorial Hospital, Chicago, IL; Madan Jagasia, Vanderbilt University, Nashville, TN; David Kleiner, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Stephanie J. Lee, Fred Hutchinson Cancer Research Center, Seattle, WA; Paul J. Martin, Fred Hutchinson Cancer Research Center, Seattle, WA; George B. McDonald, Fred Hutchinson Cancer Research Center, Seattle, WA; Joseph P. McGuirk, University of Missouri, Kansas City, MO; Sandra Mitchell, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Dietger W. Niederwieser, University of Leipzig, Leipzig, Germany; Tan T. Nguyen, Office of Orphan Products Development, Food and Drug Administration, Rockville, MD; Donna Przepiorka, University of Tennessee, Memphis, TN; Christoph Rader, Center for Cancer Research, National Cancer Institute, Bethesda, MD ; Pavan Reddy, University of Michigan, Ann Arbor, MI; Kirk R. Schultz, University of British Columbia, Vancouver, BC, Canada; Sam S. Shekar, Office of Extramural Research, Office of Director, NIH, Bethesda, MD; Warren D. Shlomchik, Yale University School of Medicine, New Haven, CT; Howard Shulman, Fred Hutchinson Cancer Research Center, Seattle, WA; Janine A. Smith, National Eye Institute, Bethesda, MD; ∗Dr. Holler and Dr. Vogelsang contributed substantially to presentations at this meeting, although they were unable to attend personally.Georgia B. Vogelsang, Johns Hopkins University School of Medicine, Baltimore, MD; Daniel Weisdorf, University of Minnesota, Minneapolis, MN; Eva M. Weissinger, Hannover Medical School, Hannover, Germany; Daniel Wolff, University of Rostock, Rostock, Germany Gorgun Akpek, University of Maryland, Baltimore, MD; Robert Baitty, Health Resources and Services Administration (HRSA), Rockville, MD; F. Javier Bolanos-Meade, Johns Hopkins University School of Medicine, Baltimore, MD; Sivasubramanian Baskar, Center for Cancer Research, National Cancer Institute, Bethesda, MD; L. Michelle Bennett, Office of the Director, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Rachel J. Bishop, National Eye Institute, NIH, Bethesda, MD; Henry Chang, National Heart, Lung and Blood Institute, NIH, Bethesda, MD; Nelson J. Chao, Duke University Medical Center, Durham, NC; Edward W. Cowen, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Manuel B. Datiles, National Eye Institute, NIH, Bethesda, MD; Nancy L. DiFronzo, National Heart, Lung and Blood Institute, NIH, Bethesda, MD; Patricia A. Dinndorf, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD; Raymond A. Dionne, National Institute for Nursing Research, NIH, Bethesda, MD; John F. DiPersio, Washington University, St. Louis, MO; Jane M. Fall-Dickson, National Institute for Nursing Research, NIH, Bethesda, MD; Daniel H. Fowler, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Nancy L. Geller, National Heart, Lung and Blood Institute, NIH, Bethesda, MD; Andrew Gilman, University of North Carolina, Chapel Hill, NC; Jean-Pierre Guadagnini, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD; Robert J. Hartzman, Naval Medical Research Center, Rockville, MD; Lee Ann Jensen, National Cancer Institute, Bethesda, MD; Laura Johnston, Stanford University School of Medicine, Stanford, CA; Carrie Lynn Kitko, University of Michigan, Ann Arbor, MI; Robert Korngold, Hackensack University Medical Center, Hackensack, NJ; Li Li, Clinical Center, NIH, Bethesda, MD; Haresh Mani, Center for Cancer Research, National Cancer Institute, Bethesda, MD; James G. McNamara, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD; William D. Merritt, National Cancer Institute, NIH, Bethesda, MD; Phyllis I. Mitchell, National Heart, Lung and Blood Institute, NIH, Bethesda, MD; Tan T. Nguyen, Office of Orphan Products Development, Food and Drug Administration, Rockville, MD; Iskra Pusic, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Scott D. Rowley, Hackensack University Medical Center, Hackensack, NJ; Benjamin I. Rubin, National Eye Institute, NIH, Bethesda, MD; Denise Russo, Office of Extramural Research, Office of the Director, NIH, Bethesda, MD; Robert A. Sokolic, National Human Genome Research Institute, NIH, Bethesda, MD; Maria L. Turner, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Marcel R. M. van den Brink, Memorial Sloan Kettering Cancer Center, New York, NY; Dan Wang, Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, MN; Alan S. Wayne, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Kirsten M. Williams, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Josiah F. Wedgwood, National Institute of Allergy and Infectious Diseases, Bethesda, MD; Roy S. Wu, National Cancer Institute, Bethesda, MD.