Tumour immunotherapy using an adenoviral vector expressing a membrane-bound mutant of murine TNFα (original) (raw)

Gene Therapy volume 4, pages 1181–1188 (1997)Cite this article

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 6 print issues and online access

$259.00 per year

only $43.17 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

Author information

Authors and Affiliations

  1. Department of Pathology, McMaster University, 1280 Main Street West, Hamilton, L8S 4K1, Ontario, Canada
    RA Marr, D Snider, J Gauldie & FL Graham
  2. Department of Biology, McMaster University, 1280 Main Street West, Hamilton, L8S 4K1, Ontario, Canada
    CL Addison, WJ Muller & FL Graham

Authors

  1. RA Marr
    You can also search for this author inPubMed Google Scholar
  2. CL Addison
    You can also search for this author inPubMed Google Scholar
  3. D Snider
    You can also search for this author inPubMed Google Scholar
  4. WJ Muller
    You can also search for this author inPubMed Google Scholar
  5. J Gauldie
    You can also search for this author inPubMed Google Scholar
  6. FL Graham
    You can also search for this author inPubMed Google Scholar

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

Download citation

Keywords

This article is cited by