title: Phase I clinical trial of costimulated, IL-4 polarized donor CD4+ T cells as augmentation of allogeneic hematopoietic cell transplantation.
abstract: The primary objective of this clinical trial was to evaluate the safety, feasibility, and biologic effects of administering costimulated, interleukin (IL)-4 polarized donor CD4(+) T cells in the setting of HLA-matched sibling, T cell-replete allogeneic hematopoietic cell transplantation (HCT). Forty-seven subjects with hematologic malignancy received granulocyte colony-stimulating factor-mobilized allogeneic hematopoietic cell transplants and cyclosporine graft-versus-host disease (GVHD) prophylaxis after reduced intensity conditioning. Initial subjects received no additional cells (n = 19); subsequent subjects received additional donor CD4(+) T cells generated ex vivo by CD3/CD28 costimulation in medium containing IL-4 and IL-2 (administered day 1 after HCT at 5, 25, or 125 x 10(6) cells/kg). Studies after HCT included measurement of monocyte IL-1alpha and tumor necrosis factor alpha, detection of T cells with antitumor specificity, and characterization of T cell cytokine phenotype. The culture method generated donor CD4(+) T cells that secreted increased T helper 2 (Th2) cytokines and decreased T helper 1 (Th1) cytokines. Such Th2-like cells were administered without infusional or dose-limiting toxicity. The Th2 cohort had accelerated lymphocyte reconstitution; both cohorts had rapid hematopoietic recovery and alloengraftment. Acute GVHD and overall survival were similar in the Th2 and non-Th2 cohorts. Th2 cell recipients tended to have increased monocyte IL-1alpha and had increased tumor necrosis factor alpha secretion. CD8(+) T cells with antitumor specificity were observed in Th2 and non-Th2 cohorts. Post-transplantation T cells from Th2 cell recipients secreted IL-4 and IL-10 (Th2 cytokines) and IL-2 and interferon gamma (Th1 cytokines). Allograft augmentation with costimulated, IL-4-polarized donor CD4(+) T cells resulted in activated Th1, Th2, and inflammatory cytokine pathways without an apparent increase in GVHD.
authors.affiliation: Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892, USA. dhfowler@helix.nih.gov
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
authors.forename: Jeanne
authors.initials: J
authors.lastname: Odom
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Catherine K
authors.initials: CK
authors.lastname: Chow
authors.forename: Jason
authors.initials: J
authors.lastname: Foley
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kogan
authors.forename: Jeannie
authors.initials: J
authors.lastname: Hou
authors.forename: Juan
authors.initials: J
authors.lastname: Gea-Banacloche
authors.forename: Claude
authors.initials: C
authors.lastname: Sportes
authors.forename: Steven
authors.initials: S
authors.lastname: Pavletic
authors.forename: Susan
authors.initials: S
authors.lastname: Leitman
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Read
authors.forename: Charles
authors.initials: C
authors.lastname: Carter
authors.forename: Arne
authors.initials: A
authors.lastname: Kolstad
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fox
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Beatty
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gress
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bishop
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D014184:Transplantation, Homologous / Q000379:methods
chemical_list: D016207:Cytokines; C508598:IL4 protein, human; D015847:Interleukin-4