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. Gress & 1 others Michael R. Bishop

Research output: Contribution to journalArticle

51 Citations (Scopus)

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
Externally publishedYes

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Clinical Trials, Phase I
Cell Transplantation
Interleukin-4
T-Lymphocytes
Cytokines
Th2 Cells
Graft vs Host Disease
Interleukin-1
Interleukin-2
Monocytes
Tumor Necrosis Factor-alpha
T-Cell Antigen Receptor Specificity
Granulocyte Colony-Stimulating Factor
Hematologic Neoplasms
Interleukin-10
Interferons
Cyclosporine
Allografts
Transplantation
Clinical Trials

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Phase I Clinical Trial of Costimulated, IL-4 Polarized Donor CD4+ T Cells as Augmentation of Allogeneic Hematopoietic Cell Transplantation. / Fowler, Daniel H.; Odom, Jeanne; Steinberg, Seth M.; Chow, Catherine K.; Foley, Jason; Kogan, Yelena; Hou, Jeannie; Gea-Banacloche, Juan; Sportes, Claude; Pavletic, Steven; Leitman, Susan; Read, Elizabeth J.; Carter, Charles; Kolstad, Arne; Fox, Rebecca; Beatty, Gregory L.; Vonderheide, Robert H.; Levine, Bruce L.; June, Carl H.; Gress, Ronald E.; Bishop, Michael R.

In: Biology of Blood and Marrow Transplantation, Vol. 12, No. 11, 01.11.2006, p. 1150-1160.

Research output: Contribution to journalArticle

Fowler, DH, Odom, J, Steinberg, SM, Chow, CK, Foley, J, Kogan, Y, Hou, J, Gea-Banacloche, J, Sportes, C, Pavletic, S, Leitman, S, Read, EJ, Carter, C, Kolstad, A, Fox, R, Beatty, GL, Vonderheide, RH, Levine, BL, June, CH, Gress, RE & Bishop, MR 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, vol. 12, no. 11, pp. 1150-1160. https://doi.org/10.1016/j.bbmt.2006.06.015
Fowler, Daniel H. ; Odom, Jeanne ; Steinberg, Seth M. ; Chow, Catherine K. ; Foley, Jason ; Kogan, Yelena ; Hou, Jeannie ; Gea-Banacloche, Juan ; Sportes, Claude ; Pavletic, Steven ; Leitman, Susan ; Read, Elizabeth J. ; Carter, Charles ; Kolstad, Arne ; Fox, Rebecca ; Beatty, Gregory L. ; Vonderheide, Robert H. ; Levine, Bruce L. ; June, Carl H. ; Gress, Ronald E. ; Bishop, Michael R. / Phase I Clinical Trial of Costimulated, IL-4 Polarized Donor CD4+ T Cells as Augmentation of Allogeneic Hematopoietic Cell Transplantation. In: Biology of Blood and Marrow Transplantation. 2006 ; Vol. 12, No. 11. pp. 1150-1160.
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