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Updated: Aug 24, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Trans-complementing adenoviral vectors for oncolytic therapy of malignant melanoma
G W Wolkersdörfer1, J C Morris, G Ehninger
1Medical Department I, Faculty of Medicine, Technical University of Dresden, 01307 Dresden, Germany. wolkersdoerfer@mk1.med.tu-dresden.de
Background:
Despite attempts to develop efficient viral-based gene transfer therapies for the treatment of malignant tumors, only limited progress has been made to improve the efficacy of this approach. As an alternative, the use of replicating oncolytic adenoviruses with and without the expression of therapeutic transgenes is an area of active investigation.
Methods:
We used a human melanoma xenograft tumor nude mouse model to test the efficacy of a bivalent vector approach consisting of two trans-complementing replication-incompetent adenoviral vectors that resulted in tumor-restricted oncolysis. We combined an E1-deleted non-replicating adenoviral vector expressing the herpes simplex virus thymidine kinase gene (AV.C2.TK) and Ad5.dl1014, an E4-deleted/E4orf4-only expressing adenovirus, to allow full replication competence when tumor cells were co-infected with both vectors.
Results:
A375 tumors showed apoptosis at the ultrastructural level after transduction with the trans-complementing vector system that was not seen with injection of either vector alone. Apoptotic DNA fragments could be co-localized to sites of infection with the adenoviral vectors. A significant survival benefit was achieved for the trans-complementing vector treated animals compared to animals treated with either vector alone. Interestingly, the administration of GCV did not further increase animal survival over treatment with the trans-complementing system of viruses alone, and long-term survival was only seen in the trans-complementing vector treatment group. Intraperitoneal administration of a pseudo-wild-type vector Ad.dl327 resulted in significant hepatotoxicity, while intraperitoneal administration of the trans-complementing vectors resulted in only mild liver abnormalities.
Conclusions:
The trans-complementing vector approach using a combination of E1- and E4-deleted adenoviral vectors showed similar antitumor efficacy as reported for monovalent replicating vector systems, but may offer additional safety by reducing the risk of dissemination of the replication-competent vectors by requiring the presence of both vectors in a cell to achieve replication competence.
Insights
This study shows a new bivalent adenoviral vector system for cancer therapy. The combined vectors effectively target tumors, leading to significant survival benefits in mice with reduced liver toxicity.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Cancer research
Background:
- Viral gene therapy for tumors has limited efficacy.
- Replicating oncolytic adenoviruses are under investigation for cancer treatment.
Purpose of the Study:
- To evaluate a bivalent vector system for tumor-restricted oncolysis.
- To assess the efficacy and safety of trans-complementing replication-incompetent adenoviral vectors.
Main Methods:
- A human melanoma xenograft mouse model was used.
- A combination of E1-deleted (AV.C2.TK) and E4-deleted (Ad5.dl1014) adenoviral vectors was employed.
- Tumor cell co-infection enabled replication competence.
Main Results:
- The trans-complementing vector system induced tumor cell apoptosis and DNA fragmentation.
- Significant survival benefit was observed in treated animals compared to single-vector treatment.
- Hepatotoxicity was minimal with the bivalent system, unlike a pseudo-wild-type vector.
Conclusions:
- The bivalent adenoviral vector approach demonstrates effective antitumor efficacy.
- This system offers enhanced safety by requiring dual-vector presence for replication.
- It provides an alternative to monovalent replicating vectors with reduced dissemination risk.
