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Published on: November 24, 2014
Selectively replicating adenoviruses for oncolytic therapy
T K Yoon1, T Shichinohe, S Laquerre
1Institute for Genetic Medicine and Department of Biochemistry, University of Southern California Keck School of Medicine, Los Angeles, CA, 90033, USA.
Abstract:
The most prevalent problem in cancer therapy is the regrowth and metastasis of malignant cells after standard treatment with surgery, radiation, and/or chemotherapy. Gene therapy approaches have suffered from the inadequate transduction efficiencies of replication-defective vectors that have been used thus far. Replication-competent vectors, particularly adenoviruses that cause cytolysis as part of their natural life cycle, represent an emerging technology that shows considerable promise as a novel treatment option, particularly for locally advanced or recurrent cancer. A number of oncolytic adenoviruses that are designed to replicate selectively in tumor cells by targeting molecular lesions inherent in cancer, or by incorporation of tissue-specific promoters driving the early genes that initiate viral replication, are currently being tested in clinical trials. The results of these clinical trials indicate that, in its current form, oncolytic adenovirus therapy shows the best results and achieves an enhanced tumoricidal effect when used in combination with chemotherapeutic agents such as cisplatin, leucovorin and 5-fluorouracil. Nevertheless, each of the oncolytic adenoviruses in current use exhibits characteristic shortcomings, and there is still considerable room for improvement. Current strategies for improving the selectivity and efficacy of oncolytic adenoviruses include molecular engineering of tumor cell-specific binding tropism, selective modifications of viral early genes and incorporation of cellular promoters to achieve tumor-specific replication, augmentation of anti-tumor activity by incorporation of suicide genes, and manipulation of the immune response.
Insights
Replication-competent oncolytic adenoviruses show promise for treating recurrent cancers. Combining these novel gene therapies with chemotherapy enhances tumor cell destruction, though further improvements are needed.
Area of Science:
- Oncology
- Gene Therapy
- Virology
Background:
- Cancer recurrence and metastasis remain significant challenges in oncology.
- Traditional cancer therapies like surgery, radiation, and chemotherapy often face limitations due to inadequate transduction efficiencies of replication-defective vectors.
- Replication-competent vectors, specifically adenoviruses, offer a promising approach due to their natural cytolytic capabilities.
Purpose of the Study:
- To explore the potential of oncolytic adenoviruses as a novel cancer treatment.
- To evaluate the efficacy of oncolytic adenoviruses, particularly in combination with chemotherapy, for advanced or recurrent cancers.
- To identify current limitations and future strategies for enhancing oncolytic adenovirus therapy.
Main Methods:
- Development of oncolytic adenoviruses engineered for selective replication in tumor cells.
- Targeting molecular lesions inherent in cancer or using tissue-specific promoters for viral replication.
- Clinical trials evaluating oncolytic adenovirus therapy, often in combination with chemotherapeutic agents.
Main Results:
- Oncolytic adenoviruses demonstrate enhanced tumoricidal effects when combined with chemotherapeutic agents like cisplatin, leucovorin, and 5-fluorouracil.
- Clinical trials indicate oncolytic adenovirus therapy is a promising option for locally advanced or recurrent cancers.
- Current oncolytic adenoviruses exhibit limitations, necessitating further research and development.
Conclusions:
- Oncolytic adenovirus therapy, especially when combined with chemotherapy, offers a potent strategy against cancer recurrence and metastasis.
- Ongoing research focuses on molecular engineering to improve adenovirus selectivity, efficacy, and immune response modulation.
- Further advancements in oncolytic adenovirus design are crucial for overcoming existing shortcomings and maximizing therapeutic benefits.
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