By Nishka Mahajan
Cancer is one of the world’s leading causes of death, caused by changes in gene expression with consequent impacts on cell proliferation. Owing to modern-day innovative recombinant DNA technologies, gene therapy can be used to provide the patient with a correct copy of the defective gene – promising a new therapeutic strategy for cancer treatment. This technique employs a ‘vehicle’ to deliver the therapeutic gene to the targeted cell. In recent years, adenovirus-based gene therapies have widely been explored in pre-clinical and clinical trials.1, 2
Adenoviruses (Ads) are composed of a linear double-stranded DNA genome (35 kb) packaged in a non-enveloped icosahedral capsid of about 90 nm in diameter. Several features make Ads an ideal vehicle for gene therapy. Ads are well characterized, with a broad cellular tropism – can efficiently infect both dividing and non-dividing cells. To alter the tropism specificity, their capsids can be further genetically modified. Moreover, genome modifications enable the expression of various transgenes. Lastly, Ads naturally induce an immune response that is a hallmark of the expansive utility of Ads for cancer gene therapy agents.3
Prospective strategies of gene therapy that are currently being used to target cancer include:
Ad vectors have been engineered to carry transgenes that code for a tumour suppressor protein (p53) or proteins that induce apoptosis or cell cycle arrest. When the cell’s DNA repair mechanisms are insufficient to repair DNA damage, wild type p53 inhibits the activation of oncogenes and causes programmed cell death (apoptosis), which limits the growth of cancer. Therefore, suppression of p53 function is common in human cancers. Examples of such Ad vectors include Gendicine and Advexin, administered combined with radiotherapy, chemotherapy, and other conventional treatment regimens – demonstrating an increase in treatment sensitivity of infected cells.2, 3
Replication competent – oncolytic Ads
The principal idea behind this approach is that the Ad vector is engineered to undergo oncolytic replication in cancer cells, taking advantage of properties unique to the same. For example, the first oncolytic Ad vector to be examined in clinical trials was ONYX-015. It was engineered to be able to replicate in tumour cells that lacked p53 and were unable to infect healthy cells that expressed p53. Thereby, the virus specifically infects and leads to lysis of cancer cells by undergoing preferential lytic replication.2, 3
Suicide gene therapy
An adenoviral vector expressing the herpes simplex virus (HSV) thymidine kinase (TK) gene is used in combination with the guanosine analogue, ganciclovir (GCV) to treat human prostate cancer, leukaemia and glioblastomas. On administering GCV, the drug is phosphorylated with the aid of TK into GCV-monophosphate and further by cellular kinases into di- and triphosphate forms. While the cell is dividing, this GCV triphosphate is incorporated into the DNA strand, eventually resulting in programmed cell death.2, 3
Pre-existing immunity to particular Ad vectors in the human population, whether through natural infection or vaccination, is a significant barrier to their application in cancer therapy. When used for liver/muscle gene therapy, there was a strong immune response that led to the development of antibodies (reducing transgene expression). In the case of administering Ad vectors for the treatment of ornithine transcarbamylase deficiency – a strong immune response (because of pre-existing antibodies) caused the patient to experience a septic shock followed by complete organ failure.4 Therefore, to overcome such challenges, Ad vectors have been modified to develop ones that are less immunogenic. Advances in technology have also led to heterologous prime-boosting strategies, an approach where similar antigens are delivered through different vectors.5 This induces a more robust immune response, allowing the heterologous prime-boosted vector to avoid being affected by the pre-existing immunity against the vector.1
To summarize, different methods of modifying Ad vectors can be used for cancer treatment, including modifying Ads to deliver transgenes that code for the tumor suppressor gene (p53) and other proteins with roles in cell cycle arrest. Alternatively, Ads preferentially replicate in cancer cells and can be modified to express tumor-specific antigens, cytokines, and other immune-modulatory molecules (inducing programmed cell death). However, their usage is limited because of pre-existing immunity to the Ad vector administered, so novel strategies for overcoming the challenges of using Ad vectors in gene therapy must be developed on a continuous basis.
- Das SK, Menezes ME, Bhatia S, et al. Gene Therapies for Cancer: Strategies, Challenges and Successes. Journal of cellular physiology. 2015;230(2): 259-271. https://doi.org/10.1002/jcp.24791.
- Tseha ST. Role of Adenoviruses in Cancer Therapy. Frontiers in Oncology. 2022;12. https://doi.org/10.3389/fonc.2022.772659.
- Biegert GW, Shaw AR, Suzuki M. Current development in adenoviral vectors for cancer immunotherapy. Molecular Therapy – Oncolytics. 2021;23: 571-581. https://doi.org/10.1016/j.omto.2021.11.014.
- Sibbald B. Death but one unintended consequence of gene-therapy trial. Canadian Medical Association Journal. 2001;164(11): 1612. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC81135/.
- Fournillier A, Frelin L, Jacquier E, et al. A heterologous prime/boost vaccination strategy enhances the immunogenicity of therapeutic vaccines for hepatitis C virus. Journal of infectious diseases. 2013;208(6): 1008-1019. https://doi.org/10.1093/infdis/jit267.