Intratumoral administration of low doses of an adenovirus vector encoding tumor necrosis factor alpha together with naive dendritic cells elicits significant suppression of tumor growth without toxicity Journal Article


Authors: Kianmanesh, A.; Hackett, N. R.; Lee, J. M.; Kikuchi, T.; Korst, R. J.; Crystal, R. G.
Article Title: Intratumoral administration of low doses of an adenovirus vector encoding tumor necrosis factor alpha together with naive dendritic cells elicits significant suppression of tumor growth without toxicity
Abstract: Although tumor necrosis factor alpha (TNF-alpha) is a potent cytokine with a myriad of innate immune antitumor properties, systemic administration of TNF-alpha is associated with significant toxicity, limiting the use of the TNF-alpha protein as an antitumor therapeutic. On the basis of the knowledge that dendritic cells (DCs) play a central role in initiating antitumor adaptive immune responses, we hypothesized that intratumoral administration of low doses of an adenovirus encoding TNF-alpha (AdTNF-alpha) together with syngeneic DCs would act synergistically to suppress preexisting tumors. As a model, four different tumor cell lines, all resistant in vitro to the TNF-alpha protein, were implanted in syngeneic mice, and established tumors received intratumor AdTNF-alpha alone or in combination with DCs. At high doses (10(9) PFU), AdTNF-alpha alone suppressed tumor growth, but was associated with systemic toxicity. A 100-fold lower AdTNF-alpha concentration (10(7) PFU) or high doses of the control vector AdNull had no systemic toxicity, but also minimal suppression of tumor growth. In contrast, local administration of the low dose (10(7) PFU) of AdTNF-alpha in combination with syngeneic DCs (AdTNF-alpha + DCs) elicited marked tumor suppression without toxicity. Administration of AdTNF-alpha + DCs into tumors elicited tumor-specific cytotoxic T cells and protected animals against subsequent challenge with the same tumor, suggesting that AdTN-F-alpha + DC therapy induced tumor-specific adaptive immune host responses. Consistent with this concept, studies with syngeneic knockout mice showed that MHC class I molecules on DCs as well as CD8(+) T cells were necessary for the antitumor effect of intratumor AdTNF-alpha + DCs. These data demonstrate that the combination of intratumoral. administration of the TNF-alpha cDNA together with naive DCs can evoke tumor suppression without systemic toxicity, providing a new paradigm for the use of TNF-alpha as antitumor therapy.
Keywords: interferon-gamma; perfusion; phase-i trial; prostate-cancer; ionizing-radiation; factor receptor; antitumor immunity; hepatic; cystic-fibrosis; mediated gene-transfer; human tnf-alpha
Journal Title: Human Gene Therapy
Volume: 12
Issue: 17
ISSN: 1043-0342
Publisher: Mary Ann Liebert, Inc  
Date Published: 2001-11-01
Start Page: 2035
End Page: 2049
Language: English
ACCESSION: WOS:000172423200001
DOI: 10.1089/10430340152677395
PROVIDER: wos
PUBMED: 11747595
Notes: Article -- Source: Wos
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MSK Authors
  1. Robert J Korst
    26 Korst
  2. Jay Moon Lee
    5 Lee