title: IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia.
abstract: Disease relapse or progression is a major cause of death following umbilical cord blood (UCB) transplantation (UCBT) in patients with high-risk, relapsed or refractory acute lymphoblastic leukemia (ALL). Adoptive transfer of donor-derived T cells modified to express a tumor-targeted chimeric antigen receptor (CAR) may eradicate persistent disease after transplantation. Such therapy has not been available to UCBT recipients, however, due to the low numbers of available UCB T cells and the limited capacity for ex vivo expansion of cytolytic cells. We have developed a novel strategy to expand UCB T cells to clinically relevant numbers in the context of exogenous cytokines. UCB-derived T cells cultured with interleukin (IL)-12 and IL-15 generated >150-fold expansion with a unique central memory/effector phenotype. Moreover, UCB T cells were modified to both express the CD19-specific CAR, 1928z, and secrete IL-12. 1928z/IL-12 UCB T cells retained a central memory-effector phenotype and had increased antitumor efficacy in vitro. Furthermore, adoptive transfer of 1928z/IL-12 UCB T cells resulted in significantly enhanced survival of CD19(+) tumor-bearing SCID-Beige mice. Clinical translation of CAR-modified UCB T cells could augment the graft-versus-leukemia effect after UCBT and thus further improve disease-free survival of transplant patients with B-cell ALL.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Pegram
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Purdon
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: van Leeuwen
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Curran
authors.affiliation: 1] Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA [3] Weill Cornell Medical College, New York, NY, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Giralt
authors.affiliation: 1] Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA [3] Weill Cornell Medical College, New York, NY, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Barker
authors.affiliation: 1] Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Center for Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA [3] Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Brentjens
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D005312:Fetal Blood / Q000166:cytology*; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism*; D019409:Interleukin-15 / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000628:therapy; D012008:Recurrence; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019076:Transgenes
chemical_list: D018941:Antigens, CD19; D016207:Cytokines; D019409:Interleukin-15; D018664:Interleukin-12