Phase I clinical trial of costimulated, IL-4 polarized donor CD4+ T cells as augmentation of allogeneic hematopoietic cell transplantation.
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.
Fowler
Daniel H
DH
Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892, USA. dhfowler@helix.nih.gov
Odom
Jeanne
J
Steinberg
Seth M
SM
Chow
Catherine K
CK
Foley
Jason
J
Kogan
Yelena
Y
Hou
Jeannie
J
Gea-Banacloche
Juan
J
Sportes
Claude
C
Pavletic
Steven
S
Leitman
Susan
S
Read
Elizabeth J
EJ
Carter
Charles
C
Kolstad
Arne
A
Fox
Rebecca
R
Beatty
Gregory L
GL
Vonderheide
Robert H
RH
Levine
Bruce L
BL
June
Carl H
CH
Gress
Ronald E
RE
Bishop
Michael R
MR
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
D016207:Cytokines; C508598:IL4 protein, human; D015847:Interleukin-4