Biologic response modulation by tumor necrosis factor alpha (TNFα) in a phase Ib trial in cancer patients

Theodore Logan, William E. Gooding, Theresa L. Whiteside, Marc S. Ernstoff, Sandra S. Kaplan, Linda Miketic, Daniel R. Vlock, Cheryl Tompkins, Debra L. Wood, Paul I. Nadler, John M. Kirkwood

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

During a phase I study of recombinant human tumor necrosis factor (TNF) in cancer patients, serial immune studies were performed and analyzed for effects of TNF. The TNF (specific activity 9.6 x 106 U/mg protein, 2. Immunologic testing was performed before therapy three times and subsequently on days 2, 8, 10, 12, 29, 33, 50, 54, 71, 75, and off-study two times. Immune parameters evaluated included cytotoxicity [natural killer (NK), spontaneous lymphokine activated killer cells (LAK), LAK, and monocyte], cytokine production [spontaneous and stimulated interferon (IFN)-γ, and interleukin (IL)-2], superoxide production [resting and stimulated polymorphonuclear leukocytes (PMN) and mononuclear cells (MNC)], and phenotype of peripheral blood lymphocyte subsets (CD3, CD4, CD8, CD16, CD56, CD19). Data were analyzed for long-term effects, the effect after 1 day of treatment (day 1), and for weekly effect (change from day 1 to day 5 of a given treatment week). Significant decreases were seen in the spontaneous cytotoxicity of peripheral blood NK cells and IL-2-inducible LAK cells, whereas increases in spontaneous peripheral blood LAK activity were seen with TNF treatment. Consistent increases in superoxide production of resting PMN and MNC were demonstrated, with late increases in superoxide production by opsonized, zymosan-treated PMN. No spontaneous IFN-γ, or IL-2 were noted in sera with treatment, but production of IL-2 by MNCs rose with TNF treatment. During 5 days of TNF treatment, the percentages of circulating CD8+ and CD56+ cells decreased, whereas that of CD4+ and CD19+ cells increased significantly and consistently, as determined by a multivariate analysis. Significant changes in several independently measured parameters were observed, including a dose- related diminished production of IFN-γ by MNC stimulated by phytohemagglutinin and increased in vitro-generated LAK activity. Because there was no clinical response in this trial, no association of immunologic change with clinical response can be made. No biologically optimal dose of TNF was evident. The data suggest that TNF may act as a trigger cytokine, initiating a broad immune/inflammatory response.

Original languageEnglish (US)
Pages (from-to)387-398
Number of pages12
JournalJournal of Immunotherapy
Volume20
Issue number5
StatePublished - 1997
Externally publishedYes

Fingerprint

Lymphokine-Activated Killer Cells
Tumor Necrosis Factor-alpha
Interleukin-2
Neoplasms
Superoxides
Interferons
Neutrophils
Activated Killer Monocytes
Blood Cells
Therapeutics
Cytokines
Zymosan
Lymphocyte Subsets
Phytohemagglutinins
Natural Killer Cells
Multivariate Analysis
Phenotype
Serum
Proteins

Keywords

  • Cytokine production
  • Humans
  • Immune parameters
  • LAK
  • NK
  • Superoxide
  • T celI
  • TNF

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Immunology

Cite this

Logan, T., Gooding, W. E., Whiteside, T. L., Ernstoff, M. S., Kaplan, S. S., Miketic, L., ... Kirkwood, J. M. (1997). Biologic response modulation by tumor necrosis factor alpha (TNFα) in a phase Ib trial in cancer patients. Journal of Immunotherapy, 20(5), 387-398.

Biologic response modulation by tumor necrosis factor alpha (TNFα) in a phase Ib trial in cancer patients. / Logan, Theodore; Gooding, William E.; Whiteside, Theresa L.; Ernstoff, Marc S.; Kaplan, Sandra S.; Miketic, Linda; Vlock, Daniel R.; Tompkins, Cheryl; Wood, Debra L.; Nadler, Paul I.; Kirkwood, John M.

In: Journal of Immunotherapy, Vol. 20, No. 5, 1997, p. 387-398.

Research output: Contribution to journalArticle

Logan, T, Gooding, WE, Whiteside, TL, Ernstoff, MS, Kaplan, SS, Miketic, L, Vlock, DR, Tompkins, C, Wood, DL, Nadler, PI & Kirkwood, JM 1997, 'Biologic response modulation by tumor necrosis factor alpha (TNFα) in a phase Ib trial in cancer patients', Journal of Immunotherapy, vol. 20, no. 5, pp. 387-398.
Logan T, Gooding WE, Whiteside TL, Ernstoff MS, Kaplan SS, Miketic L et al. Biologic response modulation by tumor necrosis factor alpha (TNFα) in a phase Ib trial in cancer patients. Journal of Immunotherapy. 1997;20(5):387-398.
Logan, Theodore ; Gooding, William E. ; Whiteside, Theresa L. ; Ernstoff, Marc S. ; Kaplan, Sandra S. ; Miketic, Linda ; Vlock, Daniel R. ; Tompkins, Cheryl ; Wood, Debra L. ; Nadler, Paul I. ; Kirkwood, John M. / Biologic response modulation by tumor necrosis factor alpha (TNFα) in a phase Ib trial in cancer patients. In: Journal of Immunotherapy. 1997 ; Vol. 20, No. 5. pp. 387-398.
@article{8846cc281fa14477bff93b843861cb2b,
title = "Biologic response modulation by tumor necrosis factor alpha (TNFα) in a phase Ib trial in cancer patients",
abstract = "During a phase I study of recombinant human tumor necrosis factor (TNF) in cancer patients, serial immune studies were performed and analyzed for effects of TNF. The TNF (specific activity 9.6 x 106 U/mg protein, 2. Immunologic testing was performed before therapy three times and subsequently on days 2, 8, 10, 12, 29, 33, 50, 54, 71, 75, and off-study two times. Immune parameters evaluated included cytotoxicity [natural killer (NK), spontaneous lymphokine activated killer cells (LAK), LAK, and monocyte], cytokine production [spontaneous and stimulated interferon (IFN)-γ, and interleukin (IL)-2], superoxide production [resting and stimulated polymorphonuclear leukocytes (PMN) and mononuclear cells (MNC)], and phenotype of peripheral blood lymphocyte subsets (CD3, CD4, CD8, CD16, CD56, CD19). Data were analyzed for long-term effects, the effect after 1 day of treatment (day 1), and for weekly effect (change from day 1 to day 5 of a given treatment week). Significant decreases were seen in the spontaneous cytotoxicity of peripheral blood NK cells and IL-2-inducible LAK cells, whereas increases in spontaneous peripheral blood LAK activity were seen with TNF treatment. Consistent increases in superoxide production of resting PMN and MNC were demonstrated, with late increases in superoxide production by opsonized, zymosan-treated PMN. No spontaneous IFN-γ, or IL-2 were noted in sera with treatment, but production of IL-2 by MNCs rose with TNF treatment. During 5 days of TNF treatment, the percentages of circulating CD8+ and CD56+ cells decreased, whereas that of CD4+ and CD19+ cells increased significantly and consistently, as determined by a multivariate analysis. Significant changes in several independently measured parameters were observed, including a dose- related diminished production of IFN-γ by MNC stimulated by phytohemagglutinin and increased in vitro-generated LAK activity. Because there was no clinical response in this trial, no association of immunologic change with clinical response can be made. No biologically optimal dose of TNF was evident. The data suggest that TNF may act as a trigger cytokine, initiating a broad immune/inflammatory response.",
keywords = "Cytokine production, Humans, Immune parameters, LAK, NK, Superoxide, T celI, TNF",
author = "Theodore Logan and Gooding, {William E.} and Whiteside, {Theresa L.} and Ernstoff, {Marc S.} and Kaplan, {Sandra S.} and Linda Miketic and Vlock, {Daniel R.} and Cheryl Tompkins and Wood, {Debra L.} and Nadler, {Paul I.} and Kirkwood, {John M.}",
year = "1997",
language = "English (US)",
volume = "20",
pages = "387--398",
journal = "Journal of Immunotherapy",
issn = "1524-9557",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Biologic response modulation by tumor necrosis factor alpha (TNFα) in a phase Ib trial in cancer patients

AU - Logan, Theodore

AU - Gooding, William E.

AU - Whiteside, Theresa L.

AU - Ernstoff, Marc S.

AU - Kaplan, Sandra S.

AU - Miketic, Linda

AU - Vlock, Daniel R.

AU - Tompkins, Cheryl

AU - Wood, Debra L.

AU - Nadler, Paul I.

AU - Kirkwood, John M.

PY - 1997

Y1 - 1997

N2 - During a phase I study of recombinant human tumor necrosis factor (TNF) in cancer patients, serial immune studies were performed and analyzed for effects of TNF. The TNF (specific activity 9.6 x 106 U/mg protein, 2. Immunologic testing was performed before therapy three times and subsequently on days 2, 8, 10, 12, 29, 33, 50, 54, 71, 75, and off-study two times. Immune parameters evaluated included cytotoxicity [natural killer (NK), spontaneous lymphokine activated killer cells (LAK), LAK, and monocyte], cytokine production [spontaneous and stimulated interferon (IFN)-γ, and interleukin (IL)-2], superoxide production [resting and stimulated polymorphonuclear leukocytes (PMN) and mononuclear cells (MNC)], and phenotype of peripheral blood lymphocyte subsets (CD3, CD4, CD8, CD16, CD56, CD19). Data were analyzed for long-term effects, the effect after 1 day of treatment (day 1), and for weekly effect (change from day 1 to day 5 of a given treatment week). Significant decreases were seen in the spontaneous cytotoxicity of peripheral blood NK cells and IL-2-inducible LAK cells, whereas increases in spontaneous peripheral blood LAK activity were seen with TNF treatment. Consistent increases in superoxide production of resting PMN and MNC were demonstrated, with late increases in superoxide production by opsonized, zymosan-treated PMN. No spontaneous IFN-γ, or IL-2 were noted in sera with treatment, but production of IL-2 by MNCs rose with TNF treatment. During 5 days of TNF treatment, the percentages of circulating CD8+ and CD56+ cells decreased, whereas that of CD4+ and CD19+ cells increased significantly and consistently, as determined by a multivariate analysis. Significant changes in several independently measured parameters were observed, including a dose- related diminished production of IFN-γ by MNC stimulated by phytohemagglutinin and increased in vitro-generated LAK activity. Because there was no clinical response in this trial, no association of immunologic change with clinical response can be made. No biologically optimal dose of TNF was evident. The data suggest that TNF may act as a trigger cytokine, initiating a broad immune/inflammatory response.

AB - During a phase I study of recombinant human tumor necrosis factor (TNF) in cancer patients, serial immune studies were performed and analyzed for effects of TNF. The TNF (specific activity 9.6 x 106 U/mg protein, 2. Immunologic testing was performed before therapy three times and subsequently on days 2, 8, 10, 12, 29, 33, 50, 54, 71, 75, and off-study two times. Immune parameters evaluated included cytotoxicity [natural killer (NK), spontaneous lymphokine activated killer cells (LAK), LAK, and monocyte], cytokine production [spontaneous and stimulated interferon (IFN)-γ, and interleukin (IL)-2], superoxide production [resting and stimulated polymorphonuclear leukocytes (PMN) and mononuclear cells (MNC)], and phenotype of peripheral blood lymphocyte subsets (CD3, CD4, CD8, CD16, CD56, CD19). Data were analyzed for long-term effects, the effect after 1 day of treatment (day 1), and for weekly effect (change from day 1 to day 5 of a given treatment week). Significant decreases were seen in the spontaneous cytotoxicity of peripheral blood NK cells and IL-2-inducible LAK cells, whereas increases in spontaneous peripheral blood LAK activity were seen with TNF treatment. Consistent increases in superoxide production of resting PMN and MNC were demonstrated, with late increases in superoxide production by opsonized, zymosan-treated PMN. No spontaneous IFN-γ, or IL-2 were noted in sera with treatment, but production of IL-2 by MNCs rose with TNF treatment. During 5 days of TNF treatment, the percentages of circulating CD8+ and CD56+ cells decreased, whereas that of CD4+ and CD19+ cells increased significantly and consistently, as determined by a multivariate analysis. Significant changes in several independently measured parameters were observed, including a dose- related diminished production of IFN-γ by MNC stimulated by phytohemagglutinin and increased in vitro-generated LAK activity. Because there was no clinical response in this trial, no association of immunologic change with clinical response can be made. No biologically optimal dose of TNF was evident. The data suggest that TNF may act as a trigger cytokine, initiating a broad immune/inflammatory response.

KW - Cytokine production

KW - Humans

KW - Immune parameters

KW - LAK

KW - NK

KW - Superoxide

KW - T celI

KW - TNF

UR - http://www.scopus.com/inward/record.url?scp=0031464924&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031464924&partnerID=8YFLogxK

M3 - Article

VL - 20

SP - 387

EP - 398

JO - Journal of Immunotherapy

JF - Journal of Immunotherapy

SN - 1524-9557

IS - 5

ER -