By Charlotte Hutchings
Despite extensive attempts and advances in therapy, cancer remains a substantial global health problem. In 2018, there were an estimated 18.1 million new cancer cases and 9.6 million cancer-related deaths worldwide (Bray et al., 2018). Evidently, current treatment modalities are insufficient and novel cancer therapeutics would be highly desirable. Gene therapy is a biological approach to treat, prevent or diagnose disease through the use of recombinant DNA. Since the introduction of gene therapy to the clinic in the 1990s, nearly two-thirds of gene therapy trials have aimed to manage various forms of cancer (Ginn et al., 2018).
In the early days of gene therapy, many regarded this novel approach as a revolution in medicine. It was believed that the ability to solve disease at its genetic cause, rather than simply treating the symptoms, would allow us to cure almost any human disease (Mountain, 2000). Unfortunately, it soon became clear that this was not the case. Indeed, in the first decade of gene therapy researchers discovered a number of unexpected hurdles, many of which were related to the efficiency of gene transfer vectors. In 1995, an expert committee assembled by the National Institute of Health suggested that funding should be re-directed away from clinical trials using these inefficient vectors and put toward more basic scientific studies of gene expression and gene transfer (Wadman, 1995). Furthermore, following an unanticipated immune response to an adenoviral vector, the first gene therapy death was reported in 1999 leaving the fate of gene therapy very much up in the air (Mountain, 2000).
Nevertheless, researchers persisted and refined gene therapy procedures to ensure their safety leading to the first commercially approved gene therapy hitting the market in 2003. The therapy, named Gendicine, was a non-replicative adenoviral vector engineered to carry a functional human p53 gene. With approval from the Chinese State Food and Drug Administration, the therapy was administered to patients with head and neck squamous cell carcinoma (Wirth et al., 2013). Of note, this approval was given without data from a standard phase III clinical trial, thus leading to debate about efficacy and limiting investment in Gendicine elsewhere in the world. In fact, it was not until 2017 that the U.S. Food and Drug Administration (FDA) gave commercial market approval to a gene therapy. Again, this gene therapy was for to be used in cancer management, this time treatment of B-cell lymphoma and B-cell acute lymphoblastic leukaemia (Philippidis, 2017). Here, T-lymphocytes are removed from patients and modified ex-vivo using a lentiviral vector encoding the CD19-specific chimeric antigen receptor (CAR). Cells are re-administered to the patient where recognition of CD19 on cancer cells leads to activation of an anti-cancer T-cell response.
With continuous advances being made in the field, particularly the production of more efficient vectors, several strategies of gene therapy are being investigated in order to target all the major hallmarks of cancer. The most commonly used approach in the treatment of solid tumours is that of ‘suicide gene therapy’. This method involves the delivery of a gene encoding either (i) a cytotoxic protein that reduces the viability of cells to promote suicide, or (ii) an enzyme that has the ability to convert a prodrug into a lethal drug within the cancerous cell (Navarro et al., 2016). An example of the latter is the delivery of herpes simplex virus thymidine kinase (HSV-TK) which converts ganciclovir into a phosphorylated form that is further metabolized into a toxic triphosphate molecule, inhibiting DNA synthesis and causing cell death (Hossain et al., 2018). Although the U.S. FDA are yet to approve suicide gene therapy for widespread use, clinical trials are ongoing. In addition, using suicide gene therapy alongside traditional treatment modalities, such as chemotherapy, is an increasingly attractive route to promote efficiency and safety whilst reducing treatment side effects.
Another upcoming form of cancer gene therapy is the use of oncolytic viruses (OVs). These viruses, most commonly adenoviruses, are modified such that their replication is confined specifically to cancer cells, thus allowing accumulation and lysis. As well as this direct killing of cancer cells, the release of cell debris following lysis contributes to the stimulation of a host immune response against the tumour (Goradel et al., 2018). Following the recognition of this immune interaction, much effort has been put into combining the use of OVs with the stimulation of immune response, a method referred to as oncolytic immunotherapy (Raja et al., 2018). For example, OVs can be engineered to deliver cytokine/chemokine genes such as those encoding granulocyte-macrophage colony stimulating factor (GM-CSF), IL-12, IL-2 and tumour necrosis factor (TNF)-a. In the case of CG0070 (a conditionally replicating oncolytic adenovirus carrying the GM-CSF gene) intratumoural injection in xenograft tumour models resulted in induction of cancer cell apoptosis and significantly reduced tumour volume (Ramesh et al., 2006). The first FDA approval of an OV was that of talimogene laherparepvec (T-VEC) in 2015. This modified herpes simplex virus type 1 carries the GM-CSF gene and is used to treat melanoma patients (Goradel et al., 2018).
Regardless of the cancer gene therapy approach being investigated, there are several shared challenges being faced in this field. The most important, designing improved vectors, is common to all gene therapies. Gene transfer vectors should have a high transfection efficiency, low immunogenicity, cost-effectiveness and cell/tissue specificity (Navarro et al., 2016). The latter is being addressed in multiple ways including the use of tissue-specific promotors and, in the case of viral vectors, small deletions to ensure that the viral vector can only replicate in cancerous cells (Goradel et al., 2018). Transfection efficiency is being improved by reducing the elimination of viral vectors from circulation. One way in which this is being done is through the use of cellular carriers which act as a ‘Trojan horses’, hiding constructs from neutralizing antibodies and complement proteins (Cejalvo et al., 2018). However, there has also been an increased interest in the generation of non-viral vectors, given their balance between safety and efficiency. Other additional strategies are also being trialled in the development of safer and more efficient cancer gene therapies.
The road to successful gene therapies has undoubtably been longer than expected, but we are now beginning to successfully translate three decades of research into clinical application. Currently, in excess of 4,500 gene therapy trials have been, or are in the process of being conducted, and approximately 2,500 of these trials have been focused on cancer (Clinical trials NIH, 2020). Whilst there will never be a global ‘cure’ for cancer, one of the most complex diseases encountered in humans, gene therapy could play a pivotal role in addressing cancer’s major genetic causes.
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. & Jemal, A. (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 68, 394-424. doi: 10.3322/caac.21492.
Cejalvo, T., Perisé-Barrios, A. J., del Portillo, I., Laborda, E., Rodriguez-Milla, M. A., Cubillo, I., Vázquez, F., Sardón, D., Ramirez, M., Alemany, R., del Castillo, N. & García-Castro, J. (2018) Remission of spontaneous canine tumors after systemic cellular viroimmunotherapy. Cancer Research (Chicago, Ill.). 78, 4891-4901. doi: 10.1158/0008-5472.can-17-3754.
Ginn, S. L., Amaya, A. K., Alexander, I. E., Edelstein, M. & Abedi, M. R. (2018) Gene therapy clinical trials worldwide to 2017: An update. The Journal of Gene Medicine. 20, e3015-n/a. doi: 10.1002/jgm.3015.
Goradel, N. H., Mohajel, N., Malekshahi, Z. V., Jahangiri, S., Najafi, M., Farhood, B., Mortezaee, K., Negahdari, B. & Arashkia, A. (2018) Oncolytic adenovirus: A tool for cancer therapy in combination with other therapeutic approaches. Journal of Cellular Physiology. 234, 8636-8646. doi: 10.1002/jcp.27850.
Hossain, J. A., Riecken, K., Miletic, H. & Fehse, B. (2018) Cancer suicide gene therapy with TK.007. In: Anonymous. Suicide Gene Therapy. New York, NY, Springer New York. pp. 11-26.
Mountain, A. (2000) Gene therapy: the first decade. England, Elsevier Ltd.
Navarro, S. A., Carrillo, E., Griñán-Lisón, C., Martín, A., Perán, M., Marchal, J. A. & Boulaiz, H. (2016) Cancer suicide gene therapy: A patent review. Expert Opinion on Therapeutic Patents. 26, 1095-1104. doi: 10.1080/13543776.2016.1211640.
Philippidis, A. (2017) Kymriah, first CAR-T cancer immunotherapy approved by FDA. Clinical Omics. 4, 8. doi: 10.1089/clinomi.04.05.09.
Raja, J., Ludwig, J. M., Gettinger, S. N., Schalper, K. A. & Kim, H. S. (2018) Oncolytic virus immunotherapy: Future prospects for oncology. Journal for Immunotherapy of Cancer. 6, 140. doi: 10.1186/s40425-018-0458-z.
Ramesh, N. (2006) CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor-armed oncolytic adenovirus for the treatment of bladder cancer. Clinical Cancer Research. 12, 305-313. doi: 10.1158/1078-0432.ccr-05-1059.
US National Library of Medicine, Clinical Trials Website. http://www.clinicaltrials.gov [1 Novemeber 2020]
Wadman, M. (1995) Hyping results ‘could damage’ gene therapy. Nature. 378, 655. doi: 10.1038/378655a0.
Wirth, T., Parker, N. & Ylä-Herttuala, S. (2013) History of gene therapy. Gene. 5