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.
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 AdTNF-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.
Kianmanesh
A
A
Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Hackett
N R
NR
Lee
J M
JM
Kikuchi
T
T
Korst
R J
RJ
Crystal
R G
RG
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002455:Cell Division; D002470:Cell Survival; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage*; D016219:Immunotherapy, Adoptive / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000627:therapeutic use*
D014409:Tumor Necrosis Factor-alpha