Heat-inducible amplifier vector for high-level expression of granulocyte-macrophage colony-stimulating factor

Pascal Dammeyer, Melba C. Jaramillo, Brian L. Pipes, Michael S. Badowski, Tom C. Tsang, David T. Harris

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose: In cytokine immunotherapy of cancer it is critical to deliver sufficiently high local cytokine concentrations in order to reach the therapeutic threshold needed for clinical efficacy. Simultaneously, for optimal clinical safety adverse effects caused by high systemic cytokine levels must be minimized. One of the most promising anti-cancer therapeutic cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF), has elicited anti-tumour immune responses in animal studies and clinical trials. However, the clinical efficacy has been limited, with local GM-CSF levels being therapeutically insufficient and systemic toxicity being a limiting factor. Methods: To address these problems we have developed a novel GM-CSF expression vector, pAD-HotAmp-GM-CSF, which can provide high levels of GM-CSF expression, and induction of cytokine expression to limited tissue areas. This expression system combines inducible and amplifying elements in a single multi-genic construct. The first transcriptional unit contains the inducible element, the heat shock protein 70B (HSP70B) promoter that regulates expression of the transcription-activating factor tat. Results: Upon the binding of tat to the second promoter, the HIV2 long terminal repeat amplifies downstream gene expression of the therapeutic cytokine GM-CSF. Moderate hyperthermia at 42°C for 30 min induced GM-CSF expression in pAD-HotAmp-GM-CSF that was over 2.5- and 2.8-fold higher than levels reached with HSP70B promoter alone and the prototypical human cytomegalovirus promoter. Conclusions: Thus, the inducible amplifier vector, pAD-HotAmp-GM-CSF, represents a novel system for regulated and enhanced GM-CSF expression, which enables both greater efficacy and safety in cytokine immunotherapy of cancer.

Original languageEnglish (US)
Pages (from-to)407-419
Number of pages13
JournalInternational Journal of Hyperthermia
Volume22
Issue number5
DOIs
StatePublished - Aug 2006

Fingerprint

Granulocyte-Macrophage Colony-Stimulating Factor
Hot Temperature
Cytokines
Heat-Shock Proteins
Immunotherapy
Neoplasms
Activating Transcription Factors
Safety
Terminal Repeat Sequences
Cytomegalovirus
Fever
Therapeutics
Clinical Trials
Gene Expression

Keywords

  • Amplifier vector
  • GM-CSF
  • Hyperthermia
  • Inducible
  • Localized expression

ASJC Scopus subject areas

  • Cancer Research
  • Radiological and Ultrasound Technology

Cite this

Heat-inducible amplifier vector for high-level expression of granulocyte-macrophage colony-stimulating factor. / Dammeyer, Pascal; Jaramillo, Melba C.; Pipes, Brian L.; Badowski, Michael S.; Tsang, Tom C.; Harris, David T.

In: International Journal of Hyperthermia, Vol. 22, No. 5, 08.2006, p. 407-419.

Research output: Contribution to journalArticle

Dammeyer, Pascal ; Jaramillo, Melba C. ; Pipes, Brian L. ; Badowski, Michael S. ; Tsang, Tom C. ; Harris, David T. / Heat-inducible amplifier vector for high-level expression of granulocyte-macrophage colony-stimulating factor. In: International Journal of Hyperthermia. 2006 ; Vol. 22, No. 5. pp. 407-419.
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AB - Purpose: In cytokine immunotherapy of cancer it is critical to deliver sufficiently high local cytokine concentrations in order to reach the therapeutic threshold needed for clinical efficacy. Simultaneously, for optimal clinical safety adverse effects caused by high systemic cytokine levels must be minimized. One of the most promising anti-cancer therapeutic cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF), has elicited anti-tumour immune responses in animal studies and clinical trials. However, the clinical efficacy has been limited, with local GM-CSF levels being therapeutically insufficient and systemic toxicity being a limiting factor. Methods: To address these problems we have developed a novel GM-CSF expression vector, pAD-HotAmp-GM-CSF, which can provide high levels of GM-CSF expression, and induction of cytokine expression to limited tissue areas. This expression system combines inducible and amplifying elements in a single multi-genic construct. The first transcriptional unit contains the inducible element, the heat shock protein 70B (HSP70B) promoter that regulates expression of the transcription-activating factor tat. Results: Upon the binding of tat to the second promoter, the HIV2 long terminal repeat amplifies downstream gene expression of the therapeutic cytokine GM-CSF. Moderate hyperthermia at 42°C for 30 min induced GM-CSF expression in pAD-HotAmp-GM-CSF that was over 2.5- and 2.8-fold higher than levels reached with HSP70B promoter alone and the prototypical human cytomegalovirus promoter. Conclusions: Thus, the inducible amplifier vector, pAD-HotAmp-GM-CSF, represents a novel system for regulated and enhanced GM-CSF expression, which enables both greater efficacy and safety in cytokine immunotherapy of cancer.

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