Gene therapy targets the root of the disease by correcting the abnormal gene. Gene therapy is the process of replacing defective or cancerous genes (also called “oncogenes”) with normal genes. The removal of these oncogenes reprograms the cell to its normal state, preventing tumor growth and the spread of cancer.  
Cancer is a group of diseases in which the body's normal self-regulatory mechanisms no longer control the growth of some kinds of cells. Cells are frequently exposed to a variety of agents, from both external and internal sources, which damage DNA. Even minor DNA damage can have profound effects, causing certain genes to become overactive, to undergo partial or complete inactivation, or to function abnormally. Genes control a number of protective pathways in cells that prevent cells from becoming cancerous. For example, pathways that transmit signals for a cell to divide have on-off switches that control cell division. Cells also have mechanisms that allow them to determine if their DNA has been damaged, and they have pathways to repair that damage or eliminate the cell. The failure of any of these protective pathways can lead to the development of cancer.

Gendicine’ is the world’s first gene therapy drug approved for clinical application by governmental agency for the treatment of cancer indications.   

Gendicine. Gendicine™, a p53 adenovirus for the treatment of head- and neck squamous cell cancer is used in combination with radiotherapy. After the approval of Gendicine™ by the SFDA, there has been intensive discussion about the efficiency of the treatment and lack of details in the reporting.

This replication-incompetent adenovirus contains the p53 transgene in place of the viral E1 region, under a Rous sarcoma virus promoter together with a bovine growth hormone poly(A)-tail, produced in a bioreactor using human embryonic kidney cells and purified with chromatographical methods.
In a phase I clinical trial with 12 laryngeal cancer patients, only one patient resulted in self-limited fever and none of the patients had tumor relapse during the 5 year follow-up after the treatment (15,10). Similarly in phase II/III trials with 132 head and neck squamous cell carcinoma patients, 32% showed fever as the only side-effect of the treatment. When Gendicine™ was used in combination with radiotherapy, 64 % of the patients responded with a complete regression and 29 % with a partial regression while with radiotherapy alone, 19 % showed a complete regression and 60 % a partial regression, suggesting synergistic effect of the combination treatment. The regression of patients was evaluated by tumor shrink rates according to WHO response criteria. However, the published details of these clinical trials are limited, making comparisons to other cancer trials difficult.

Due to the various roles of p53 protein, the authors suggested that the results derive from the role of p53 in sequence-specific transcription regulation inducing apoptosis in nucleus, mitochondria and Golgi apparatus; activating the immune system, inhibiting DNA repair and downregulating drug resistance-genes and vascular endothelial growth factors.

The latest released data of Gendicine indicate that out of 26 patients with Gendicine and radiotherapy, 17 have survived for 5 years and 16 without any recurrence, while in the control group of 27 patients 14 survived for 5 years with 10 without any recurrence. These numbers are too small to draw any conclusions about the efficiency of Gendicine, yet there are claims that over 7000 patients have already been treated but there is no data about official phase IV study. 

Mechanism of Action:
Gendicine is a gene therapy drug used to treat a wide variety of cancers. It is mainly composed of replication-incompetent recombinant Ad-p53 virus particles, which based on adenovirus serotype 5 and human wild-type p53 tumor suppressor gene, a key housekeeping gene, coding human wild-type P53 protein. In normal cells the expression level of P53 protein is very low, but it will be activated upon DNA damage. The up-regulation of p53 gene expression occurs at the post-translational level, and is achieved through stabilization of the protein. Upon induction, the main outcome of P53 protein activation is either cell cycle arrest or apoptotic cell death. While some tumors do not express p53, others express a mutant form of the P53 protein. p53 gene mutation rate in human tumors is up to 50~70%. Mutant forms of the P53 are not necessarily inactive, and can carry out several characteristic functions that contribute to tumorigenicity.

Post-injection intratumorally Gendicine enters tumor cells through adenovirus infection-mediated endocytosis and its carried exogenous p53 gene begins to express. Over-expressed P53 protein exerts its role of induction of tumor cell cycle arrest or apoptosis depending on the ability of P53 protein to act as sequence specific transcriptional regulator to up-regulate the expression of numerous anti-cancer genes and down-regulate the expression of numerous oncogenes. It can also directly induce the apoptosis of tumor cells without acting as transcriptional regulator to regulate any gene expression. Moreover over-expressed P53 protein acts effectively as a tumor antigen in stimulating human immune cells to assemble in tumor tissues and to selectively kill cancer cells over-expressing the p53 gene (by CTL cells) or to kill those uninfected cancer cells (by NK cells) via bystander effects. Addition to the above, it can down-regulate the expression of vascular endothelial growth factor (VEGF) gene and MDR gene, which involve respectively in the progress and metastasis of tumors or in the multi-drug resistance of tumors. By virtue of lack of DNA damage, exogenous p53 gene will not express in a normal cell, and therefore Gendicine does no harm to it.

Pharmacokinetics:
The results of in vivo animal experiments showed that these recombinant adenoviral DNA particles administrated locally or systemically have entered tumor cells within 1 hour post-injection. At 3rd hour post-injection p53 gene began to express and P53 protein was detectable. The expression rate of p53 gene increased to 47% at 12th hour, and reached the highest level at 72nd hour, then descended to 30% at 120th hour. But its expression was still detectable at 14th day. At 3 weeks post-injection the recombinant adenoviral DNA began to be digested and disintegrated. While been injected locally Gendicine distributed mainly in local tissue, and can be hardly detected in other organs and tissues. No recombinant adenoviral DNA was detected in excrements of urine, stool, or bile.

Clinical Studies: 
Phase I clinical trial of intratumoral administration of Gendicine in patients with laryngeal squamous cell carcinoma was completed in Beijing Tongren Hospital to identify its safety. The results indicated that the main side effect was fever at the dose of 1ⅹ1012VP (virus particles). So the recommended dosage which should be adopted in phase II clinical trial was 1x1012vp/injection/week.
By November 2005, 4-6 years follow-up result of the 12 patients participated in the phase I clinical trial showed that 11/12 patients were alive with median survival time of 5.9 years. Follow-up time ranged from 4.0 to 6.4 years and 5-year survival rate of 91.7%. One patient aged 79 when enrolled into the clinical trial (the oldest one in the clinical trial) with poor-moderate differentiation squamous cell carcinoma died of the metastasis to liver at the age of 83 (4 years survived). It was reported by Am. Joint Committee on Cancer (AJCC) on 2002 that 5-year survival rate of laryngeal squamous cell carcinoma was 68.6-71.1% in stage I, 55.5-59.9% in stage II, and 46.4-50.1% in stage III, it was reported by Ji WenYue that it was generally 69.96% in different stages of laryngeal squamous cell carcinoma domestically.

A multicenter, randomized, open-label, parallel design phase II/III clinical trial was conducted in which patients with head and neck squamous cell carcinoma (HNSCC), the majority (85%) of them had nasopharyngeal cancer, were divided randomly into two groups: one group received gene therapy in combination with radiotherapy (GTRT) and the other group received radiotherapy alone (RT). There were no significant differences (p>0.05) in age, sex, or clinical stage, or in size of tumor lesion between the two groups of patients. Conventional or three-dimensional conformal radiotherapy was used at doses of 70 Gy administered in 35 fractions over 7–8 weeks for the RT group. For the GTRT group, Gendicine was given each week at a dose of 1×1012 VP 3 days before radiotherapy, for a total of 8 weeks. Radiotherapy in the GTRT group was the same as that used in the RT group. Objective tumor response was evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) according to tumor response criteria World Health Organization (WHO) . The data showed that the response rate in the GTRT group was 93%, with 64% showing complete regression (CR) and 29% partial regression (PR). The response rate in the RT group was 79% with 19% of the patients showing CR and 60% PR. There is a significant difference (p<0.01) between the two groups in terms of both the CR rate and the PR rate. The CR rate in the GTRT group was 3-fold higher than that in the RT group. We concluded that Gendicine in combination with radiotherapy showed obviously synergistic effects.

By September 2005, the follow-up was carried out for 78 patients participated in the phase II/III clinical trial including 40 cases in the GTRT group and 38 cases in the RT Group. The mean follow-up time was 39.4 months. The results showed that the median disease-free survival time, 3-year disease-free survival rate and 3-year overall survival rate are 38 months, 74.3% and 78.8% respectively in the GTRT group and 32 months, 61.7% and 69.4% in the RT group.

In the phase I and II/III clinical trials, the main side effect noted was only grade I/II self-limited fever, beginning within 2-4 hours post-injection and lasting about 2-6 hours, in near 80% cases or in 32% person-times. The 3 to 6 years follow-up results showed no other side effects and special symptoms or syndromes for survival patients.

Indications:
Gendicine is approved by SFDA for the treatment of nasopharyngeal carcinoma in combination with radiotherapy.
Based on the clinical trial results in more than 20 varieties of malignant tumors worldwide, recombinant human adenovirus p53 product has been used to treat solid tumors alone or in combination with radiotherapy, chemotherapy or other therapies.  

Oncorine

Oncorine™ for treating head and neck cancer (H101) is a conditionally replicative adenovirus, with a deletion in E1B 55K region, therefore restricting the virus to bind and inactivate wild-type p53 protein. Inactivation of the host cell p53 is essential for wild-type adenoviruses to disable the activation of apoptotic pathway when host cell shifts to S phase in the lytic infection. When E1B 55K activity is removed, the replication in normal cells is blocked, allowing only replication in p53-deficient cells. In malignant cells the viral proliferation leads to oncolysis, used as a cancer therapy to treat solid tumours.

In phase I trials, Oncorine™ showed tumor shrinking with 3 patients out of 15 with good safety (1 partial regression and 2 with minor response). With phase II trials of 53 patients, the treatment group (two cycles of intratumoral injection of Oncorine™) showed 28 % response rate against the 12 % of control (no data available), again well tolerated (3 with complete regression and 11 with partial regression). Finally, in phase III trials with 123 patients in treatment group (combination of chemotherapy and Oncorine™) or control (chemotherapy alone), the response rate in treatment group was 72.7 %, as compared to 40.4 % of the control group. Similarly with nasopharyngeal cancer, combination treatment with chemotherapy and Oncorine™ resulted in response rate of 75.6 % against 57.1 % of the control group. The response was evaluated by the shrinkage of the tumor according to the WHO criteria.

The patient’s complications included fever, injection site pain, nausea, alopecia, leucopenia and flu-like symptoms. The authors speculate that since patients with fever showed increased response rate, the elevated temperature might improve viral replication through heat shock protein assisted late mRNA export. The criticism towards the phase III trials is focused on the small number of patients in the trial.