AAV Vectors in Cancer Gene Therapy

In recent years, many important breakthroughs have been achieved in gene therapy in many disease types, including genetic diseases and cancer. Adeno-associated virus (AAV) is one of the most active vectors for gene therapy. The trials of gene therapy mediated by AAV vectors have been performed for the treatment of multiple diseases, including cancer and monogenic, cardiovascular, neurological, ocular, and infectious diseases. The milestone of AAV-mediated clinical studies is the development of inherited retinal diseases and anerythrochloropsia gene therapy. AAV-mediated PRE65 gene expression efficiently recovered visual function in patients with Leber's congenital amaurosis with controlled safety and efficacy of gene transfer. These encouraging results broaden the clinical applications of AAV vectors, including gene therapy of cancer.

AAV Vector System for Cancer Gene Therapy

In cancer treatment, ideal gene transfer as well as expression should be restricted to the cell-type of interest such as the malignant cell or distinct cells of the tumor microenvironment like dendritic cells (DC), macrophages, endothelial cells or fibroblasts. Moreover, it would be advantageous to optimize efficacy to minimize the vector dose that needs to be applied and to be equipped for a possible re-application scenario. To achieve these goals, both the capsid and the genome of AAV vectors have become targets for engineering. In particular, transcriptional and post-transcriptional targeting, as well as transductional targeting strategies, have been developed.

Targeting strategies.

Figure 1. Targeting strategies. (Hacker U T, et al., 2020)

Changes in protein expression patterns and subsequent presentation of tumor-specific antigens in cancer tissues may allow the preferential targeting of AAV gene delivery vehicles to tumor tissues. For instance, Grifman et al. targeted aminopeptidase N (or CD13), a membrane-bound enzyme, is highly expressed in cancerous tissue and vessels, so it is used for targeted tumor therapies. There has also been a strong interest in AAV delivery to immune cells. In particular, given that cancers can produce resistance mechanisms against both drugs and the immune system, cancer research efforts have also focused on stimulating the adaptive immune system to mount a T cell-mediated anti-tumor response. Immunotherapy provides important potential advantages over traditional therapies, including selectivity for tumor cells and the generation of memory T cells that protect against recurring tumors.

Advances in AAV-mediated Cancer Gene Therapy

In the past decade, the arsenal of delivered transgenes has greatly expanded, and the types of cancer for which AAV vectors have been used. These transgenes can be divided into several types: cytotoxic or suicide genes, anti-angiogenesis genes, cytokines for stimulating the immune system, tumor suppression and anti-tumor genes, DNA encoding small RNA's, antibodies that block signaling, and antigens to stimulate antigen-presenting cells.

  • AAV-mediated suicide gene therapy

Suicide gene therapy, also known as gene-directed enzyme prodrug therapy (GDEPT) or molecular chemotherapy, is currently the most promising strategy for the genetic treatment of different cancers. GDEPT relies on the intratumor delivery of a transgene encoding an enzyme, and then activates a systemically-delivered prodrug that inhibits DNA polymerase and blocks DNA replication in tumor cells. Among the candidate genes, the herpes simplex virus thymidine kinase gene/ganciclovir prodrug (HSV-tk/GCV) system is an excellent example of the clinical application of GDEPT. Studies have suggested that the AAV-mediated HSV-tk/GCV therapeutic system generates strong antitumor efficacy.

  • AAV-mediated antiangiogenesis gene therapy

Vascular endothelial growth factor (VEGF), an important mediator of angiogenesis in both healthy and diseased tissues, is an important antitumor target. A study showed that a single intravenous administration of AAV/VEGF-Trap resulted in a long-term efficacy and permitted not only suppression of primary tumor growth but also prevention of pulmonary metastasis. AAV-mediated transduction of other antiangiogenic genes, such as pigment epithelium-derived factor (PEDF), Kringle 5, endostatin 34, and kallistatin, also showed significant inhibition of tumor angiogenesis, tumor growth, and metastasis.

  • AAV-mediated immune gene therapy

AAV-mediated immune gene therapy is based on the successful activation of the host immune system upon transfer of therapeutic genes to targets cells, including cytokines, tumor antigens, and immunogenic cell surface molecules.

  • AAV-mediated RNA interference therapy

RNA interference (RNAi) is a therapeutic biological tool in different cancers. AAV-mediated short hairpin RNA (shRNA) is widely used in gene knockdown applications. Androgen receptor (AR) is associated with prostate cancer progression. Transduction of AAV/shRNA against AR inhibits the growth of tumors, even eliminating xenograft tumors within 10 days. Moreover, systemic administration of AAV-mediated miRNA-26a resulted in the inhibition of cancer growth, induction of tumor apoptosis, and protection from disease progression.

  • Delivery of antigens for stimulating antigen-presenting cells (APCs)

AAV vectors are also used to deliver antigens to APCs and thereby elicit an immune response against tumor cells expressing that antigen, i.e. a tumor vaccine. An excellent example of AAV-mediated vaccination focused on antigens from human papilloma virus 16 (HPV16), which is associated with the development of anogenital and cervical cancer.

QVirusTM Platform, a division of Creative Biogene, can offer a series of AAV services to accelerate your cancer gene therapy projects. If you have any special requirements, please feel free to contact us.

References
1. Santiago-Ortiz J L, Schaffer D V. Adeno-associated virus (AAV) vectors in cancer gene therapy. Journal of Controlled Release, 2016, 240: 287-301.
2. Luo J, et al. Adeno-associated virus-mediated cancer gene therapy: current status. Cancer letters, 2015, 356(2): 347-356.
3. Hacker U T, et al. Towards Clinical Implementation of Adeno-Associated Virus (AAV) Vectors for Cancer Gene Therapy: Current Status and Future Perspectives. Cancers, 2020, 12(7): 1889.
4. Wang Y G, et al. Targeting adeno-associated virus and adenoviral gene therapy for hepatocellular carcinoma. World Journal of Gastroenterology, 2016, 22(1): 326.
5. Naso M F, et al. Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs, 2017, 31(4): 317-334.

For research use only. Not intended for any clinical use.

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