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High-Efficiency Transduction of Liver Cancer Cells by Recombinant Adeno-Associated Virus Serotype 3 Vectors
Published on: March 22, 2011
Oncolytic adenovirus based on serotype 3
O Hemminki1, G Bauerschmitz, S Hemmi
1Cancer Gene Therapy Group, Molecular Cancer Biology Program and Haartman Institute and Transplantation Laboratory and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
Abstract:
Oncolytic adenoviruses have been safe in clinical trials but the efficacy has been mostly limited. All published trials have been performed with serotype 5 based viruses. The expression level of the Ad5 receptor CAR may be variable in advanced tumors. In contrast, the Ad3 receptor remains unclear, but is known to be abundantly expressed in most tumors. Therefore, we hypothesized that a fully serotype 3 oncolytic adenovirus might be useful for treating cancer. Patients exposed to adenoviruses develop high titers of serotype-specific neutralizing antibodies, which might compromise re-administration. Thus, having different serotype oncolytic viruses available might facilitate repeated dosing in humans. Ad3-hTERT-E1A is a fully serotype 3 oncolytic adenovirus controlled by the promoter of the catalytic domain of human telomerase. It was effective in vitro on cell lines representing seven major cancer types, although low toxicity was seen in non-malignant cells. In vivo, the virus had anti-tumor efficacy in three different animal models. Although in vitro oncolysis mediated by Ad3-hTERT-E1A and wild-type Ad3 occurred more slowly than with Ad5 or Ad5/3 (Ad3 fiber knob in Ad5) based viruses, in vivo the virus was at least as potent as controls. Anti-tumor efficacy was retained in presence of neutralizing anti-Ad5 antibodies whereas Ad5 based controls were blocked. In summary, we report generation of a non-Ad5 based oncolytic adenovirus, which might be useful for testing in cancer patients, especially in the context of high anti-Ad5 neutralizing antibodies.
Insights
A novel serotype 3 oncolytic adenovirus, Ad3-hTERT-E1A, shows promise for cancer treatment. This virus maintains efficacy even with pre-existing anti-adenovirus type 5 antibodies, potentially enabling repeated dosing.
Area of Science:
- Oncolytic virotherapy
- Viral oncology
- Gene therapy
Background:
- Oncolytic adenoviruses, primarily serotype 5 based, show limited efficacy in clinical trials due to variable receptor expression in tumors.
- Pre-existing neutralizing antibodies against adenovirus serotype 5 can hinder treatment efficacy and limit re-administration.
- Adenovirus serotype 3 receptors are broadly expressed in tumors, suggesting potential for improved oncolytic adenovirus targeting.
Purpose of the Study:
- To develop and evaluate a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-E1A) for cancer treatment.
- To assess the efficacy of Ad3-hTERT-E1A in vitro and in vivo, particularly in the presence of anti-adenovirus type 5 antibodies.
- To explore the potential of serotype 3 adenoviruses for overcoming limitations associated with serotype 5 based oncolytic viruses.
Main Methods:
- Construction of Ad3-hTERT-E1A, a serotype 3 oncolytic adenovirus utilizing the human telomerase promoter.
- In vitro efficacy testing on cancer cell lines representing seven major cancer types and assessment of toxicity in non-malignant cells.
- In vivo anti-tumor efficacy evaluation in three distinct animal models and comparison with serotype 5 based controls in the presence of neutralizing antibodies.
Main Results:
- Ad3-hTERT-E1A demonstrated in vitro efficacy across multiple cancer types with low toxicity in normal cells.
- The virus exhibited significant anti-tumor efficacy in vivo across three animal models.
- Ad3-hTERT-E1A retained anti-tumor activity in the presence of anti-adenovirus type 5 neutralizing antibodies, unlike serotype 5 based controls.
Conclusions:
- A fully serotype 3 oncolytic adenovirus (Ad3-hTERT-E1A) has been successfully generated.
- This novel oncolytic adenovirus shows potential for treating various cancers, especially in patients with high levels of anti-adenovirus type 5 antibodies.
- The development of Ad3-hTERT-E1A offers a promising alternative for oncolytic virotherapy, potentially facilitating repeated dosing strategies.
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