Phase I Clinical Trial of Costimulated, IL-4 Polarized Donor CD4+ T Cells as Augmentation of Allogeneic Hematopoietic Cell Transplantation

Daniel H. Fowler, Jeanne Odom, Seth M. Steinberg, Catherine K. Chow, Jason Foley, Yelena Kogan, Jeannie Hou, Juan Gea-Banacloche, Claude Sportes, Steven Pavletic, Susan Leitman, Elizabeth J. Read, Charles Carter, Arne Kolstad, Rebecca Fox, Gregory L. Beatty, Robert H. Vonderheide, Bruce L. Levine, Carl H. June, Ronald E. GressMichael R. Bishop

Research output: Contribution to journalArticle

52 Scopus citations

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 × 106 cells/kg). Studies after HCT included measurement of monocyte IL-1α and tumor necrosis factor α, 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-1α and had increased tumor necrosis factor α 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 γ (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.

Original languageEnglish (US)
Pages (from-to)1150-1160
Number of pages11
JournalBiology of Blood and Marrow Transplantation
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2006

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Keywords

  • Cytokines
  • Graft versus host disease
  • Tetramers
  • Th2 cells

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Fowler, D. H., Odom, J., Steinberg, S. M., Chow, C. K., Foley, J., Kogan, Y., Hou, J., Gea-Banacloche, J., Sportes, C., Pavletic, S., Leitman, S., Read, E. J., Carter, C., Kolstad, A., Fox, R., Beatty, G. L., Vonderheide, R. H., Levine, B. L., June, C. H., ... Bishop, M. R. (2006). Phase I Clinical Trial of Costimulated, IL-4 Polarized Donor CD4+ T Cells as Augmentation of Allogeneic Hematopoietic Cell Transplantation. Biology of Blood and Marrow Transplantation, 12(11), 1150-1160. https://doi.org/10.1016/j.bbmt.2006.06.015