Introduction
Overall cancer death rates in the UK have fallen by around a fifth over the last 30 years and by 10 per cent over the last decade; this is because of advances in disease detection and treatment.Reference Hu, Coffin, Davis, Graham, Groves and Guest1 However, for many cancers, including head and neck cancer, the prognosis for patients with advanced disease is uncompromisingly poor.
Breakthroughs in the field of molecular biology have allowed a greater understanding of carcinogenesis, enabling progress in cancer prevention and treatment. Genetic changes, either inherited or acquired later in life, are the basis for uncontrolled cell proliferation that causes cancer. Gene therapy aims to treat cancer by delivering genetic sequences to the patient's cells. The mechanism for this gene delivery relies on vectors, of which viruses are the most promising type. The world's first gene therapy product (an engineered adenovirus) was licensed for clinical application in 2003.Reference Peng2
Gene therapy
Gene therapy was defined in the 2003 UK Government white paper, entitled ‘Our inheritance, our future – realising the potential of genetics in the NHS’, as ‘the deliberate introduction of genetic material into patient's cells in order to treat or prevent a disease’.3 This document suggested that gene therapy would have diverse applications, ranging from ‘cancer to coronary artery disease’, and gave hope for licensed treatments ‘within 5 to 10 years’.
Gene therapy was initially applied to inherited diseases with single gene mutations (monogenic), such as severe combined immunodeficiency disease, cystic fibrosis and haemophilia. However, permanent corrective gene expression in such illnesses has been unsuccessful, despite advances in gene editing technology. This, together with the development of leukaemia in children with severe combined immunodeficiency disease, and the death of a patient with ornithine transcarbamylase deficiency following viral gene therapy, have highlighted the limitations and potential risks of such treatments.Reference Lehrman4 With this in mind, new applications for gene therapy were considered, where transient gene delivery would more likely be achieved, and a safe and clinically significant effect be provided; such applications included cancer and cardiovascular disease.Reference Young, Searle, Onion and Mautner5
Cancer is a genetic disease, wherein normal cells undergo multiple mutations as part of an ‘onco-evolutionary process’, transforming into malignant cells. Mutations in the genes that regulate cell behaviour (proto-oncogenes and tumour suppressor genes) can lead to cell growth self-sufficiency, insensitivity to anti-growth signals, evasion of apoptosis, sustained angiogenesis, limitless replicative potential, and tissue invasion and metastases – the hallmarks of cancer.Reference Hanahan and Weinberg6 All of these changes are potential targets for gene therapy. This has resulted in cancer gene therapy dominating the gene therapy research field, with two-thirds of clinical trials being for cancer applications.Reference Edelstein, Abedi and Wixon7
However, success at clinical trial has been disappointing. This is mainly due to poor efficiency of gene transfer rather than a paucity of potential therapeutic genes.Reference Vile, Russell and Lemoine8 Strategies to overcome this have focused on modulating the host immune response to the virus, optimising existing viruses, discovering and creating new viruses, and, finally, identifying tumour-associated genes that can improve therapeutic potency.
Strategies for cancer therapy
Following the mapping of the human genome, completed in 2003, there is an extensive array of genes available as potential therapeutic transgenes for cancer gene therapy. There are three main strategies that characterise the type of gene used: corrective, cytoreductive and immunomodulatory.
Corrective strategies
Cancer is caused by mutations in oncogenes and tumour suppressor genes, resulting in uncontrolled cell growth. Corrective gene therapy attempts to block oncogene or replace tumour suppressor gene function, thereby returning cell growth to normal. The genes implicated in the initiation and progression of head and neck cancers have been extensively investigated. These genes have significant consequences on the efficacy of targeted therapeutic strategies.Reference Hunt, Barnes, Lewis, Mahfouz, Slootweg and Thompson9
Oncogenes are critical tumour-associated genes, with tumours often driven by only one oncogene mutation – the so called ‘oncogene addiction’.Reference Weinstein10 Epidermal growth factor receptor is overexpressed in more than 90 per cent of head and neck squamous cell carcinoma (SCC) cases, and its over expression is associated with poor treatment outcomes.Reference Liang, Ang, Milas, Hunter and Fan11 The epidermal growth factor receptor signalling pathway is a target of current monoclonal antibody agents such as cetuximab in head and neck cancer. It is also the focus of pre-clinical gene therapy research using viruses, such as vaccinia and measles viruses, that selectively replicate in tumours with active epidermal growth factor receptor pathways.Reference Parato, Breitbach, Le Boeuf, Wang, Storbeck and Ilkow12, Reference Zaoui, Bossow, Grossardt, Leber, Springfeld and Plinkert13
Other tumour-associated genes can be activated, overexpressed or amplified in head and neck cancer. Their action can be blocked therapeutically using small molecules, monoclonal antibodies and RNA interference. In particular, RNA interference delivery can be virally mediated, as demonstrated recently in a study using an adenovirus-based RNA expression system, which targeted VEGF, TERT and Bcl-xl genes in a nasopharyngeal pre-clinical cancer model.Reference Han, Tao, Chen, Kong and Xiao14
Tumour suppressor genes are frequently mutated in head and neck cancer; the most common proteins affected are p53, p16, p15 and NOTCH.Reference Hunt, Barnes, Lewis, Mahfouz, Slootweg and Thompson9 TP53 gene mutations are implicated in 40–60 per cent of patients with head and neck cancer, and are associated with tumour invasiveness, resistance to chemoradiotherapy and disease recurrence.Reference Brennan, Mao, Hruban, Boyle, Eby and Koch15, Reference Shiraishi, Kato, Han, Liu, Otsuka and Sakayori16 The p53 gene is thus considered to be a potential magic bullet for corrective cancer gene therapy. In 2003, the world's first gene therapy product featuring a recombinant non-replicating adenovirus expressing p53 received a government licence (Gendicine; Shenzhen SiBiono GeneTech, Shenzhen, China).Reference Peng2
Cytoreductive strategies
Cytoreductive gene therapy aims to directly or indirectly kill cancer cells, rather than correct the underlying genetic defect. This can be achieved by augmenting the effects of chemotherapy by introducing a transgene that can convert an inactive pro-drug to a potent anti-cancer agent. This is referred to as gene-directed enzyme pro-drug therapy (‘GDEPT’).Reference Hanahan and Weinberg6 This has been investigated in a phase I clinical trial in head and neck cancer patients using an adenovirus-mediated nitroreductase expression and CB1954 pro-drug strategy.Reference Searle, Chen, Hu, Race, Lovering and Grove17
Another cytoreductive strategy is the inhibition of angiogenesis, as tumours are unable to grow beyond 1–2 mm diameter without developing their own blood supply.Reference Liu, Shen, Kung and Lin18 Endostatin is a potent angiogenesis inhibitor. When delivered to a murine head and neck cancer model, endostatin, used in conjunction with low-dose cisplatin treatment, reduced in vivo tumour growth.Reference Adhim, Lin, Huang, Morishita, Nakamura and Yasui19 A vaccinia virus vector armed with an endostatin-angiostatin fusion gene demonstrated superior anti-tumour efficacy for head and neck cancer in a pre-clinical study.Reference Tysome, Wang, Alusi, Briat, Gangeswaran and Wang20
Apoptosis is a tightly regulated process of programmed cell death. It can be induced in cancer cells therapeutically through the manipulation of apoptosis-inducing ligands and pro- or anti-apoptotic molecules. Adeno-associated, virus-mediated, tumour necrosis factor (TNF) related apoptosis-inducing ligand (‘TRAIL’) expression suppressed tumour growth in a mouse head and neck cancer model; in addition, anti-tumour potency was enhanced with combination cisplatin treatment.Reference Jiang, Liu, Xiang, Ma, Liu and Liu21
Immunomodulatory strategies
The host immune response detects tumour-associated antigens, which allows cluster of differentiation 8+ cytotoxic T cells to induce tumour lysis. Cancer cells can subvert this immunosurveillance through three broad strategies of tumour escape; these have been suggested to represent a ‘seventh hallmark of cancer’.Reference Zitvogel, Tesniere and Kroemer22
One common strategy is to reduce the immunogenicity of the cancer cells by modulating the interaction of peptides, major histocompatibility complex molecules and T cell receptors – a process termed antigenic drift.Reference Bai, Liu, Li, Zheng and Liu23 Furthermore, research indicates that the down-regulation of major histocompatibility complex class I by tumour cells reduces the cancer cell sensitivity to cytotoxic T lymphocyte mediated lysis.Reference Bubenik24
A second strategy is to develop resistance to immune-mediated killing by: impairing perforin binding,Reference Lehmann, Zeis, Schmitz and Uharek25 down-regulating or mutating Fas,Reference Real, Jimenez, Kirkin, Serrano, Garcia and Canton26 and mutating TNF-related apoptosis-inducing ligand receptors in tumours.Reference Shin, Kim, Lee, Park, Kim and Park27
A final strategy is to subvert the immune response through: encouraging failure in the production of danger signals that activate dendritic cells (which can lead to the development of immunosuppressive regulatory T cells),Reference Kowalczyk28, Reference Elpek, Lacelle, Singh, Yolcu and Shirwan29 down-regulating endothelial adhesion molecules,Reference Ryschich, Schmidt, Hammerling, Klar and Ganss30 inducing tryptophan deficiency (which inhibits T cell proliferation),Reference Uyttenhove, Pilotte, Theate, Stroobant, Colau and Parmentier31 encouraging the secretion of immunosuppressive mediators (such as nitric oxide, transforming growth factor β, interleukin (IL)-10),Reference Zhang and Xu32–Reference Kawamura, Bahar, Natsume, Sakiyama and Tagawa34 promoting tumour expression of Fas ligand (which can kill infiltrating immune cells),Reference Whiteside35 and inducing the production of myeloid suppressor cells (which inhibit cluster of differentiation 8+ T cell and natural killer cell activity, and inhibit dendritic cell maturation).Reference Gallina, Dolcetti, Serafini, De Santo, Marigo and Colombo36
Gene therapy can reverse this tumour-induced immunotolerance by increasing the presentation of tumour-associated antigens or up-regulating the expression of major histocompatibility complex I.Reference Vile, Russell and Lemoine8 This has been achieved by using cytokines as transgenes, with resulting enhanced anti-tumour efficacy; for example, IL-2 and IL-12 delivery by vaccinia virus.Reference Chen, Timiryasova, Haghighat, Andres, Kajioka and Dutta-Roy37 Furthermore, clearance of the viral vector or oncolytic virus by the host immune response can be abrogated by this approach.Reference Kaufman, Rao, Irvine, Bronte, Rosenberg and Restifo38
Vectors for gene therapy
The greatest limitation to cancer gene therapy becoming an effective everyday clinical treatment modality is the accuracy and efficiency of gene transfer to the target cells.Reference Vile, Russell and Lemoine8 The ideal vector should be efficient, safe and tumour selective, preferentially affecting cancer cells and sparing normal cells.
Tumour selectivity can be achieved by administering the vector directly into the tumour (intra-tumourally), or by engineering the vector physically or genetically. The latter strategy is more attractive as it would allow for systemic administration, which would enable the treatment of inaccessible, multiple and/or metastatic lesions. However, to reach its target, the vector would have to overcome the clearance of the circulating virus by complement and reticuloendothelial cell-based mechanisms.Reference Kirn and Thorne39
The two main groups of vectors used in cancer gene therapy research are viral and non-viral. Approximately 70 per cent of clinical trials and the majority of other research to date have used viral vectors.Reference Young, Searle, Onion and Mautner5 Non-viral vectors use either physical transfection (e.g. electroporation) or particle-mediated systems (e.g. dendrimers) to introduce foreign DNA into the target cells. They are generally less immunogenic than viral vectors, and this allows for repeated administration.Reference Kaneda and Tabata40 Additionally, they are cheaper to produce; however, their major disadvantage is low transfection rates.
Viruses are obligate intracellular pathogens, which require host cell machinery to complete their life cycles to a variable extent. They have evolved over millions of years to be highly effective at infecting, replicating within and generally lysing host cells. Viruses have also developed mechanisms that allow them to subvert the host immune system and thereby increase their infectivity, such as expressing interferon γ decoy receptors. Viral vectors commonly induce mild flu-like illnesses, but have the potential for causing acute life-threatening toxicity.
Non-replicating and replicating viral vectors
Apart from different viral species, a common classification of viral vectors is whether they have the ability to replicate. Non-replicating viruses were the first viral vector systems used for the delivery of foreign genes, and most research to date has utilised such viruses.Reference Everts and van der Poel41 However, the efficacy of gene transfer of these viruses is poor, and for successful cancer treatment every tumour cell would have to be infected. The great limitation of non-replicating viruses is that each virion is only able to infect one target cell, and then is destroyed when that cell dies.
In contrast to the non-replicating viral vectors, replicating viral vectors, also known as oncolytic viruses, have shown promise for cancer treatment. Oncolytic viruses are self-replicating, tumour-selective viruses that are able to lyse cancer cells.Reference Parato, Senger, Forsyth and Bell42 The oncolytic effects of viral infections were first noted at the beginning of the last century, whereby periods of clinical remission were observed in patients with leukaemia following influenza infection.Reference Dock43 The anti-tumour efficacy of oncolytic viruses is achieved through multiple mechanisms, including direct lysis, apoptosis, expression of toxic proteins, autophagy, protein synthesis shut-down and induction of anti-tumoural immunity.Reference Wong, Lemoine and Wang44
The 1950s and 1960s witnessed clinical trials of several wild-type oncolytic viruses (first generation), including reovirus, adenovirus, vaccinia virus and Newcastle disease virus. However, it was not until 1991 that advances in molecular biology allowed the development of the first genetically-engineered, replication-selective oncolytic virus (second generation), using a herpes simplex virus.Reference Martuza, Malick, Markert, Ruffner and Coen45 Subsequent research has continued investigation into genetic modifications to the viral backbone, to improve tumour selectivity and anti-tumour potency, including arming viruses with transgenes (third generation). In 2005, China approved the world's first oncolytic virus treatment, the genetically modified adenovirus Onyx-015/dl1520, or H101, for late-stage refractory nasopharyngeal cancer, used in combination with chemotherapy.Reference Garber46
Replicating viral vector-mediated oncolysis occurs independently of apoptosis pathways and is therefore effective in apoptosis-defective cells.Reference Everts and van der Poel41 Replication-selective viruses have the ability to replicate in tumour cells, but not in normal cells. Some viruses exhibit inherent tumour selectivity, such as reoviruses and the Newcastle virus, whereas other viruses can be genetically modified to improve tumour selectivity. This can be achieved by inserting tumour-specific promoters, such as the human telomerase reverse transcriptase (‘hTERT’) promoter,Reference Chang, Zhao, Wu, Guo, Guo and Cao47 or by deleting genes that are needed for viral replication in normal cells but not in tumour cells, such as thymidine kinase.Reference McCart, Ward, Lee, Hu, Alexander and Libutti48
Thus, in the context of cancer gene therapy, replicating viral vectors differs from our original notion of viral gene therapy, whereby a viral vector is used to deliver specific gene expression only to a host tissue to correct an underlying genetic defect. Oncolytic viruses can also be armed with therapeutic genes, such as anti-angiogenic or immunomodulatory genes, to enhance their anti-tumour potency.
Gene therapy viral vectors tested
Adenoviruses
The most commonly used virus for gene therapy is the adenovirus, used for 23 per cent of gene therapy trials worldwide.Reference Ginn, Alexander, Edelstein, Abedi and Wixon49 Adenoviruses are double-stranded DNA viruses, whose natural pathogenicity is associated with only mild respiratory infections. They remain episomal and therefore do not integrate into host DNA, and there is minimal risk of insertional mutagenesis.Reference Chisholm, Bapat, Chisholm, Alusi and Vassaux50 Further advantageous properties of adenoviral vectors include: high transfection efficiency, straightforward production in high titres to good manufacturing process standards and comparably high levels of transgene expression.
However, the anti-tumour efficacy in many clinical trials has been poor. This may be due in part to dependence on the host cell coxsackievirus and adenovirus receptor for cell infection, which is down-regulated in many head and neck cancers.Reference Vorburger and Hunt51, Reference Jee, Lee, Lee, Kim, Lee and Kim52 The first generation of adenoviral vectors had deletions in the E1 region of the viral genome, rendering them replication-deficient. Successive generations of non-replicating viruses had further genes removed, improving safety and transgene capacity.Reference Harrington, Nutting and Pandha53
Gendicine
The world's first government licensed gene therapy product (Gendicine, licensed in 2003) featured a recombinant adenovirus expressing p53.Reference Peng2 Gendicine is a non-replicating virus with the deletion of E1 and E3 regions, and insertion of a human wild-type p53 expression cassette driven by a Rous sarcoma virus promoter. It is capable of restoring p53 function to cancer cells, leading to cell cycle arrest, apoptosis and the inhibition of angiogenesis with resultant tumour growth suppression.Reference Taylor and Stark54, Reference Teodoro, Evans and Green55
In a phase I trial, patients with advanced laryngeal cancer received an intra-tumoural injection of Gendicine prior to surgery. The treatment was well tolerated, with only fever and injection site pain reported. Five years post-combination treatment, no patient relapsed. In contrast, there was an accepted relapse rate of around 30 per cent in patients treated with surgery alone.Reference Han, Huang, Zhang, Yu, Wang and Ni56, Reference Lee and Moon57
Phase II trials have explored the efficacy of Gendicine used in combination with radiotherapy in patients with head and neck SCC and nasopharyngeal carcinoma.Reference Pan, Zhang, Chen, Xiao, Sun and Liu58–Reference Zhang, Xiao, Liu, Sun, Su and Li60 The virus was delivered intra-tumourally, concurrently with the radiotherapy. Again, the treatments were well tolerated, with transient fever being the most commonly reported adverse event. The combination treatment achieved an overall response rate of 97.6 per cent (66.7 per cent complete response and 30.9 per cent partial response). In comparison, the overall response rate in the radiotherapy (monotherapy) treatment group was 85.4 per cent (24.4 per cent complete response and 61 per cent partial response). Median time to recurrence was also significantly improved in the combined therapy group (73 vs 59 months).
A phase III trial, which compared dual gene therapy and radiotherapy with radiotherapy alone, demonstrated an improved overall response rate in the combination group of 96 per cent (64 per cent complete response and 32 per cent partial response) versus 80 per cent in the radiotherapy alone group (19.5 per cent complete response and 61 per cent partial response).Reference Zhang, Xiao, Liu, Sun, Su and Li59 Gendicine has been approved by the Chinese State Food and Drug Administration for use in the treatment of head and neck cancers and other solid tumours, utilised in conjunction with radiotherapy.Reference Peng2
Advexin (INGN 201, Ad5CMV-p53)
This virus is very similar to Gendicine, in that it is a non-replicating adenovirus with the E1 region replaced by a human wild-type p53 expression cassette; however, this virus has a cytomegalovirus (CMV) promoter. Advexin (Introgen Therapeutics; Austin, Texas, USA) has not received US Federal Drug Administration approval, but has been the subject of a number of clinical trials.
A phase I clinical trial examined the use of multiple intra-tumoural virus injections, utilised with and without concurrent surgical resection, in 33 patients with locally or regionally advanced recurrent head and neck cancer.Reference Clayman, el-Naggar, Lippman, Henderson, Frederick and Merritt61 Of the 17 non-surgical patients, partial responses were achieved in 2 patients and stable disease (for up to 3.5 months) was recorded in 6 patients; the remainder showed progressive disease. For those patients who underwent concurrent surgical resection, 4 (27 per cent) were disease-free after 18 months of follow up, which is a greater survival rate than would be expected for patients with recurrent resectable disease.Reference Clayman, Frank, Bruso and Goepfert62
Several phase II trials have examined this virus in patients with recurrent head and neck SCC.Reference Lee and Moon57 Monotherapy trials with low doses (trial T202) and higher doses (trial T201) reported only mild flu-like adverse reactions. In addition, its effects were dose-dependent, with longer survival duration and lower mortality rates in the higher dose group. There were objective responses to the treatment, or stable disease for more than three months, in 20 per cent of patients in the high-dose group, compared with 14 per cent in the low-dose group.
There have been two phase III trials comparing the efficacy of Advexin in patients with local or regionally recurrent head and neck SCC. Trial T301 examined 123 patients who had failed chemoradiotherapy; these patients were randomised to receive either intra-tumoural Advexin or intravenous methotrexate. Advexin resulted in increased survival (7.2 vs 2.7 months) in patients with favourable p53 biomarkers compared with patients with unfavourable biomarkers (high p53 levels with a mutated TP53 sequence).Reference Nemunaitis, Clayman, Agarwala, Hrushesky, Wells and Moore63 A second study, T302, has compared treatment with Advexin, cisplatin and 5-fluorouracil against treatment with cisplatin and 5-fluorouracil; the results of this study have not yet been published.
Oncolytic virotherapy
Onyx-015 (dl1520)
Onyx-015 is a replicating adenovirus that has deletions in the early regulator protein regions E1B-55 k and E3B. These deletions result in viral replication confined to cancer cells, which, unlike non-cancer cells, are able to efficiently export late viral RNA in the absence of E1B-55 kDa.Reference O'Shea, Johnson, Bagus, Choi, Nicholas and Shen64
In 2000, the first study of combination intra-tumoural oncolytic virotherapy and chemotherapy (cisplatin and 5-fluorouracil) in 37 patients with recurrent head and neck cancer was published.Reference Khuri, Nemunaitis, Ganly, Arseneau, Tannock and Romel65 In this phase II trial, 63 per cent of patients demonstrated overall responses and 27 per cent showed complete responses with the combination treatment. Historical data of monotherapy overall responses with chemotherapy and Onyx-015 were 35 per cent and 14 per cent respectively. The combination treatment was well tolerated, with injection site pain being the most commonly reported adverse event.
H101
H101 is another replication-competent adenovirus, with similar deletions to Onyx-015 in the E1B-55 k and E3 regions. The H101 virus is produced by Shanghai Sunway Biotech (Shanghai, China), and has been tested in patients with head and neck SCC and nasopharyngeal carcinoma.
A phase II clinical trial investigated the intra-tumoural H101 virus used in combination with chemotherapy in 46 patients with advanced cancer.Reference Xu, Yuan, Guan, Cao, Wang and Hu66, Reference Lu, Zheng, Li, Huang, Zheng and Li67 The findings demonstrated an overall response rate of 30.4 per cent, compared with a 13 per cent overall response rate for the control group. The only side effects reported were fever and injection site pain.
In a phase III study, intra-tumoural H101, used in conjunction with cisplatin and 5FU, or Adriamycin® and 5FU, was compared with the two chemotherapy regimens used without the virus.Reference Xia, Chang, Zhang, Jiang, Guan and Liu68 In the H101 plus cisplatin and 5-fluorouracil group, an overall response rate of 78.8 per cent was achieved, compared with 39.6 per cent for patients treated with chemotherapy alone.
KH901
This is another replication-competent oncolytic adenovirus, with a granulocyte-macrophage colony-stimulating factor (‘GM-CSF’) transgene under the control of a human telomerase reverse transcriptase promoter. Granulocyte-macrophage colony-stimulating factor is a cytokine that has been demonstrated to have important anti-tumour effects; these are achieved mainly through the stimulation of antigen-presenting cell proliferation, maturation and function.Reference Borrello and Pardoll69 Telomerases are overexpressed in 80–95 per cent of cancers, and are involved in maintaining cancer cell immortality.Reference Ruden and Puri70
A phase I trial administered the virus intra-tumourally to patients with recurrent head and neck cancer. The results demonstrated good treatment tolerability, granulocyte-macrophage colony-stimulating factor expression, adenovirus neutralising antibody and evidence of anti-tumour activity.Reference Chang, Zhao, Wu, Guo, Guo and Cao47
Herpes simplex virus type 1
Like adenoviruses, herpes simplex virus type 1 is a double-stranded DNA virus and does not integrate into the host genome. HSV1716 is a first-generation oncolytic virus with deletions in the neurovirulence gene ICP34.5, which restricts virus replication to tumour cells. A phase I trial of the intra-tumourally injected virus in patients with oral SCC demonstrated that the virus was well tolerated; however, there was no evidence of viral replication.Reference Mace, Ganly, Soutar and Brown71 Nevertheless, disease stabilisation in the treatment of glioma has been recorded at much higher HSV1716 virus concentrations.Reference Papanastassiou, Rampling, Fraser, Petty, Hadley and Nicoll72
OncoVEXGM-CSF is a second-generation herpes simplex virus, with deletions of the ICP34.5 and ICP47 genes. The ICP34.5-encoding sequences have been replaced with the CMV promoter and human granulocyte-macrophage colony-stimulating factor genes. ICP47 gene deletion enhances tumour-selective replication. A phase I trial delivered the virus intra-tumourally to patients with refractory solid tumours, including head and neck SCC. Biological responses of viral replication, granulocyte-macrophage colony-stimulating factor expression and tumour necrosis were recorded. Clinical responses of tumour regression and disease stabilisation were found.Reference Hu, Coffin, Davis, Graham, Groves and Guest1
Conclusion
Two viral gene therapy products have received government licences for the treatment of head and neck cancer (used in conjunction with established treatment modalities): Gendicine and H101. However, the efficacy of viral monotherapy remains poor, typically less than 20 per cent. Significant challenges remain in the development of efficient viruses with the necessary genetic modifications to allow tumour-selective replication, host immunomodulation and effective tumour lysis. The combination of viral vector based gene therapy with conventional treatment modalities is the future direction for the management of human solid tumours, including head and neck cancer. Certainly, cancer treatment personalised to the individual patient's cancer genotype remains the ultimate goal of cancer gene therapy.
