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; Michael R. Bishop

doi:10.1016/j.bbmt.2006.06.015

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 journal › Article › peer-review

56 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 language	English (US)
Pages (from-to)	1150-1160
Number of pages	11
Journal	Biology of Blood and Marrow Transplantation
Volume	12
Issue number	11
DOIs	https://doi.org/10.1016/j.bbmt.2006.06.015
State	Published - Nov 2006
Externally published	Yes

Keywords

Cytokines
Graft versus host disease
Tetramers
Th2 cells

ASJC Scopus subject areas

Hematology
Transplantation

Access to Document

10.1016/j.bbmt.2006.06.015

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

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

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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 × 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.",

keywords = "Cytokines, Graft versus host disease, Tetramers, Th2 cells",

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

note = "Funding Information: This work was supported in part by the Center for Cancer Research (D. Fowler, J. Odom, S. Steinberg, J. Foley, Y. Kogan, J. Hou, J. Gea-Banacloche, C. Sportes, S. Pavletic, R. Gress, and M. Bishop) and by a grant from the Leukemia and Lymphoma Society of America to the University of Pennsylvania Abramson Cancer Research Center (R. Fox, G. Beatty, R. Vonderheide, B. Levine, and C. June). The authors thank NIH Clinical Center, NIH Department of Transfusion Medicine, and NCI Pharmacy and Clinical Care Units for their dedication in providing care to patients on this study. They also acknowledge the contributions of Kate Castro, RN, Janine Daub, RN, Ladan Foruraghi, RN, Robert Dean, MD, Alan Wayne, MD, Frances Hakim, PhD, Barbara Vance, PhD, and Vicki Fellowes. This report is dedicated to the memory of Charles Carter as a great friend, colleague, and cell therapy pioneer in the wake of his untimely recent death.",

year = "2006",

month = nov,

doi = "10.1016/j.bbmt.2006.06.015",

language = "English (US)",

volume = "12",

pages = "1150--1160",

journal = "Biology of Blood and Marrow Transplantation",

issn = "1083-8791",

publisher = "Elsevier Inc.",

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TY - JOUR

T1 - Phase I Clinical Trial of Costimulated, IL-4 Polarized Donor CD4+ T Cells as Augmentation of Allogeneic Hematopoietic Cell Transplantation

AU - Fowler, Daniel H.

AU - Odom, Jeanne

AU - Steinberg, Seth M.

AU - Chow, Catherine K.

AU - Foley, Jason

AU - Kogan, Yelena

AU - Hou, Jeannie

AU - Gea-Banacloche, Juan

AU - Sportes, Claude

AU - Pavletic, Steven

AU - Leitman, Susan

AU - Read, Elizabeth J.

AU - Carter, Charles

AU - Kolstad, Arne

AU - Fox, Rebecca

AU - Beatty, Gregory L.

AU - Vonderheide, Robert H.

AU - Levine, Bruce L.

AU - June, Carl H.

AU - Gress, Ronald E.

AU - Bishop, Michael R.

N1 - Funding Information: This work was supported in part by the Center for Cancer Research (D. Fowler, J. Odom, S. Steinberg, J. Foley, Y. Kogan, J. Hou, J. Gea-Banacloche, C. Sportes, S. Pavletic, R. Gress, and M. Bishop) and by a grant from the Leukemia and Lymphoma Society of America to the University of Pennsylvania Abramson Cancer Research Center (R. Fox, G. Beatty, R. Vonderheide, B. Levine, and C. June). The authors thank NIH Clinical Center, NIH Department of Transfusion Medicine, and NCI Pharmacy and Clinical Care Units for their dedication in providing care to patients on this study. They also acknowledge the contributions of Kate Castro, RN, Janine Daub, RN, Ladan Foruraghi, RN, Robert Dean, MD, Alan Wayne, MD, Frances Hakim, PhD, Barbara Vance, PhD, and Vicki Fellowes. This report is dedicated to the memory of Charles Carter as a great friend, colleague, and cell therapy pioneer in the wake of his untimely recent death.

PY - 2006/11

Y1 - 2006/11

N2 - 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.

AB - 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.

KW - Cytokines

KW - Graft versus host disease

KW - Tetramers

KW - Th2 cells

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