title: Infusion of CD3/CD28 costimulated umbilical cord blood T cells at the time of single umbilical cord blood transplantation may enhance engraftment.
abstract: Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (10(5) cells/kg). At the 10(5) cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD.
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Elizabeth O
authors: EO
authors: Hexner
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Selina M
authors: SM
authors: Luger
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Ran
authors: R
authors: Reshef
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Grace R
authors: GR
authors: Jeschke
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: James K
authors: JK
authors: Mangan
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Noelle V
authors: NV
authors: Frey
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Dale M
authors: DM
authors: Frank
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Lee P
authors: LP
authors: Richman
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Robert H
authors: RH
authors: Vonderheide
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Nicole A
authors: NA
authors: Aqui
authors: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Misha
authors: M
authors: Rosenbach
authors: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors: Yi
authors: Y
authors: Zhang
authors: Center for Cellular Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Anne
authors: A
authors: Chew
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Alison W
authors: AW
authors: Loren
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Edward A
authors: EA
authors: Stadtmauer
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Center for Cellular Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Bruce L
authors: BL
authors: Levine
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Center for Cellular Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Carl H
authors: CH
authors: June
authors: Columbia College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, New York.
authors: Stephen G
authors: SG
authors: Emerson
authors: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: David L
authors: DL
authors: Porter
mesh_terms: D000328:Adult; D000754:Anemia, Refractory, with Excess of Blasts / Q000628:therapy; D053264:B-Cell Activating Factor / Q000096:biosynthesis; D001793:Blood Preservation; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002478:Cells, Cultured / Q000637:transplantation; D036101:Cord Blood Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D015925:Cryopreservation; D016207:Cytokines / Q000032:analysis; D004306:Dose-Response Relationship, Immunologic; D005240:Feasibility Studies; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology; D006648:Histocompatibility; D006801:Humans; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000628:therapy; D017710:Lymphocyte Transfusion / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008565:Membrane Proteins / Q000096:biosynthesis; D008875:Middle Aged; D009504:Neutrophils / Q000637:transplantation; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000637:transplantation*; D019172:Transplantation Conditioning / Q000379:methods; D016896:Treatment Outcome
chemical_list: D053264:B-Cell Activating Factor; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D008565:Membrane Proteins; C505719:TNFSF13B protein, human; C084881:flt3 ligand protein