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High-Efficiency Transduction of Liver Cancer Cells by Recombinant Adeno-Associated Virus Serotype 3 Vectors
Published on: March 22, 2011
Ad3-hTERT-E1A, a fully serotype 3 oncolytic adenovirus, in patients with chemotherapy refractory cancer
Otto Hemminki1, Iulia Diaconu1, Vincenzo Cerullo1
1Cancer Gene Therapy Group, Haartman Institute and Transplantation Laboratory, University of Helsinki, Helsinki, Finland.
Abstract:
Twenty-five patients with chemotherapy refractory cancer were treated with a fully serotype 3-based oncolytic adenovirus Ad3-hTERT-E1A. In mice, Ad3 induced higher amounts of cytokines but less liver damage than Ad5 or Ad5/3. In humans, the only grade 3 adverse reactions were self-limiting cytopenias and generally the safety profile resembled Ad5-based oncolytic viruses. Patients that had been previously treated with Ad5 viruses presented longer lasting lymphocytopenia but no median increase in Ad3-specific T-cells in blood, suggesting immunological activity against antigens other than Ad3 hexon. Frequent alterations in antitumor T-cells in blood were seen regardless of previous virus exposure. Neutralizing antibodies against Ad3 increased in all patients, whereas Ad5 neutralizing antibodies remained stable. Treatment with Ad3-hTERT-E1A resulted in re-emergence of Ad5 viruses from previous treatments into blood and vice versa. Signs of possible efficacy were seen in 11/15 (73%) patients evaluable for tumor markers, four of which were treated only intravenously. Particularly promising results were seen in breast cancer patients and especially those receiving concomitant trastuzumab. Taken together, Ad3-hTERT-E1A seems safe for further clinical testing or development of armed versions. It offers an immunologically attractive alternative, with possible pharmacodynamic differences and a different receptor compared to Ad5.
Insights
A novel oncolytic adenovirus (Ad3-hTERT-E1A) shows a favorable safety profile in cancer patients, similar to Ad5-based viruses. Promising signs of efficacy were observed, particularly in breast cancer patients.
Area of Science:
- Oncolytic virotherapy
- Adenovirus-based cancer treatment
- Immunotherapy
Background:
- Chemotherapy-refractory cancers present significant treatment challenges.
- Oncolytic adenoviruses are engineered viruses that selectively infect and kill cancer cells.
- Serotype 3 adenovirus (Ad3) offers an alternative to the commonly used Ad5, with potential differences in immunogenicity and toxicity.
Purpose of the Study:
- To evaluate the safety and potential efficacy of a serotype 3-based oncolytic adenovirus, Ad3-hTERT-E1A, in patients with advanced cancer.
- To compare the immunogenicity and safety profile of Ad3-hTERT-E1A with previously used Ad5-based oncolytic viruses.
- To explore the impact of Ad3-hTERT-E1A on antitumor immune responses.
Main Methods:
- A Phase I clinical trial involving 25 patients with chemotherapy-refractory cancer.
- Administration of Ad3-hTERT-E1A.
- Monitoring of adverse events, viral shedding, and immune responses (neutralizing antibodies, T-cell responses).
- Assessment of tumor marker changes as a measure of potential efficacy.
Main Results:
- Ad3-hTERT-E1A demonstrated a generally favorable safety profile, with self-limiting cytopenias as the main grade 3 adverse reactions.
- Increased neutralizing antibodies against Ad3 were observed, while Ad5 neutralizing antibodies remained stable.
- Re-emergence of previously administered Ad5 viruses was noted in some patients treated with Ad3, and vice versa.
- Signs of potential efficacy were observed in 73% of evaluable patients, with notable responses in breast cancer, especially when combined with trastuzumab.
Conclusions:
- Ad3-hTERT-E1A is safe for further clinical development and offers an immunologically distinct alternative to Ad5-based oncolytic viruses.
- The study suggests potential pharmacodynamic differences and a different receptor interaction compared to Ad5.
- Further investigation, including armed versions of Ad3-hTERT-E1A, is warranted.
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