title: Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy.
abstract: Disease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)-derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19+ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19+ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19+ B-ALL relapse.
authors.affiliation: University of Texas M. D. Anderson Cancer Center, Pediatrics Research Unit 853, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors.forename: Lisa Marie
authors.initials: LM
authors.lastname: Serrano
authors.forename: Timothy
authors.initials: T
authors.lastname: Pfeiffer
authors.forename: Simon
authors.initials: S
authors.lastname: Olivares
authors.forename: Tontanai
authors.initials: T
authors.lastname: Numbenjapon
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bennitt
authors.forename: Daniel
authors.initials: D
authors.lastname: Kim
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.forename: George
authors.initials: G
authors.lastname: McNamara
authors.forename: Zaid
authors.initials: Z
authors.lastname: Al-Kadhimi
authors.forename: Joseph
authors.initials: J
authors.lastname: Rosenthal
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000097:blood; D018941:Antigens, CD19 / Q000097:blood*; D002051:Burkitt Lymphoma / Q000276:immunology / Q000628:therapy*; D016923:Cell Death; D002470:Cell Survival; D003602:Cytotoxicity, Immunologic; D005312:Fetal Blood / Q000276:immunology* / Q000637:transplantation*; D015774:Ganciclovir / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D020014:K562 Cells; D008163:Luminescent Measurements; D008212:Lymphocyte Depletion / Q000379:methods; D017710:Lymphocyte Transfusion; D051379:Mice; D018715:Microscopy, Video; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D018941:Antigens, CD19; D015774:Ganciclovir