Abstract
The most limiting factor regarding the use of TNFα in tumour therapy is systemic toxicity. The expression of membrane-bound (nonsecreted) TNFα within a tumour may serve to reduce systemic toxicity while retaining antitumour activity. Two adenovirus (Ad) vectors were constructed: (1) Ad-mTNF-wt expressing wild-type murine TNFα; and (2) Ad-mTNF-MEM expressing a mutant nonsecreted (membrane-bound) form. Only the Ad-mTNF-wt vector induced high levels of TNFα secretion in transduced cells (approximately 400 ng/10 6 cells), however, both vectors induced efficient cell surface expression as detected by FACS. These vectors were used in tumour immunotherapy trials in a murine transgenic breast cancer model. High serum concentrations of mTNFα (approximately 1 ng/ml) were detected only in Ad-mTNF-wt-treated mice, while both vectors induced substantial disruption of tumour pathology. The wt TNF vector was highly toxic, killing 12 of 16 mice at a dose of 5 × 108 p.f.u., whereas the Ad-mTNF-MEM vector showed low toxicity killing three of 27 at the same dose. Both vectors induced partial, and in some cases, permanent tumour regressions, with cured mice displaying protective immunity and specific CTL activity against the tumour. These results indicate that the use of a nonsecreted form of TNFα can result in a relatively large reduction in systemic toxicity with little or no reduction in antitumour activity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Marr, R., Addison, C., Snider, D. et al. Tumour immunotherapy using an adenoviral vector expressing a membrane-bound mutant of murine TNFα. Gene Ther 4, 1181–1188 (1997). https://doi.org/10.1038/sj.gt.3300528
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3300528
Keywords
This article is cited by
-
Arsenic Nanoparticles are Effective in Reducing 3-Methylcholanthrene Induced Carcinogenesis in Murine Fibrosarcoma by Promoting Anti-tumorigenic Inflammation
BioNanoScience (2022)
-
Alteration in Inflammasome Cytokine Profile and Functional Plasticity of Macrophage Phenotype in Arsenic(0) Nanoparticle Treated Murine Fibrosarcoma
BioNanoScience (2022)
-
Modular assembly of synthetic proteins that span the plasma membrane in mammalian cells
BMC Biotechnology (2016)
-
Mesothelin-specific cell-based vaccine generates antigen-specific immunity and potent antitumor effects by combining with IL-12 immunomodulator
Gene Therapy (2016)
-
Cancer Immunotherapy Using a Membrane-bound Interleukin-12 With B7-1 Transmembrane and Cytoplasmic Domains
Molecular Therapy (2012)