Product case study Gendicine

Gendicine is the tradename given to the first gene-therapy-based medicine approved anywhere in the world. It gained approval for use in the treatment of head and neck squamous cell carcinoma from China's State Food and Drug Administration in 2003. This is one of the most common cancers in China. The company that developed, manufactures and markets the product is Shenzhen SiBono GeneTech, (Shenzhen, China). Gendicine is a replication-incompetent human serotype 5 adenovirus engineered to contain the native human p53 tumour suppressor gene. The product is administered by direct intratumoural injection and the standard treatment entails Gendicine administration concurrently with the application of radiotherapy.

Product manufacture entails viral vector propagation in a suitable animal packing cell line (known as HEK 293). After cell recovery and lysis, the crude product is clarified by filtration and concentrated by ultrafiltration. The product is then treated with a nuclease preparation in order to degrade contaminant DNA and further downstream processing entails multi-step highresolution column chromatography (see also Figure 14.7).

Intratumoural injection is believed to facilitate vector uptake and expression of p53 in the adjacent tumour cell, leading to cell cycle arrest and apoptosis. Company data showed complete regression of tumours in 64 per cent of patients treated with Gendicine in combination with radiation therapy, with few associated side effects. By 2006 the product was believed to have been administered to some 50 000 patients in China, and is in late-stage clinical trials for various other cancers.

A broadly similar approach to that of Gendicine is being adopted by some Western companies, including Introgen Therapeutics (USA), whose p53 adenoviral-based drug Advexin has entered phase III clinical trials for sqamous cell carcinoma in 2006.

episodes. In most instances so far, this strategy has been carried out in practice by removal of target cells from the body, culture in vitro, introduction of the desired gene (mainly using retroviral vectors), followed by reintroduction of the altered cells into the body.

An alternative anti-cancer strategy entails insertion of a copy of a tumour suppresser gene into cancer cells. For example, a deficiency in one such gene product, p53, has been directly implicated in the development of various human cancers. It has been shown in vitro that insertion of a p53 gene in some p53-deficient tumour cell lines induces the death of such cells. A potential weakness of such an approach, however, is that 100 per cent of the transformed cells would have to be successfully treated to fully cure the cancer. Tumour suppressor-based gene therapy in combination with conventional approaches (chemotherapy or radiotherapy) may, therefore, prove most efficacious, and the sole gene-therapy-based medicine approved to date (in China only) is based upon this approach (Box 14.2).

Yet another strategy that may prove useful is the introduction into tumour cells of a 'sensitivity' gene. This concept dictates that the gene product should harbour the ability to convert a non-toxic pro-drug into a toxic substance within the cells - thus leading to their selective destruction. The model system most used to appraise such an approach entails the use of the thymidine kinase gene of the herpes simplex virus (Figure 14.12).

Tumor cell

Pro-drug

Tumor cell

N

Active drug (toxic)

'Sensitivity' gene product

Pro-drug

y

V

J

s

N

GCV-TP (toxic)

Cellular kinases

GCV-MP

<

HSVtk

GCV

V

J

Figure 14.12 Schematic representation of the therapeutic rationale underpinning the introduction of a 'sensitivity' gene into tumour cells in order to promote their selective destruction. As depicted in (a), the gene product should be capable of converting an inactive pro-drug into a toxic drug capable of killing the cell. A specific example of this approach is presented in (b): introduction of the herpes simplex thymidine kinase (HSVtk) gene confers sensitivity to the anti-herpes drug, Ganciclovir (GCV) on the cell. GCV is converted by HSVtk into a monophosphorylated form (GCV-MP). This, in turn, is phosphorylated by endogenous kinases, yielding ganciclovir triphosphate (GCV-TP). GCV-TP induces cell death by inhibiting DNA polymerase. A potential advantage of this system is that some adjacent tumour cells (which themselves lack the HSVtk gene) are also destroyed. This is most likely due to diffusion of the GCV-MP or GCV-TP (perhaps via gap junctions) into such adjacent cells. This so-called 'bystander effect' means that all the transformed cells in a tumour would not necessarily need to be transduced for the therapy to be successful

A different gene therapy-based approach to cancer entails introduction of a gene into haematopoietic stem cells in order to protect these cells from the toxic effects of chemotherapy. Most cancer drugs display toxic side effects which usually limits the upper dosage levels that can be safely administered. One common toxic side-effect is the destruction of stem cells. If these cells could be protected or made resistant to the chemotherapeutic agent, it might be possible to administer higher concentrations of the drug to the patient. In practice, such a protective effect could be conferred by the multiple drug resistance (type 1; MDR-1) gene product. This is often expressed by cancer cells resistant to chemotherapy. It functions to pump a range of chemotherapeutic drugs (e.g. daunorubicin, taxol, vinblastine, vincristine, etc.) out of the cell. Animal studies have confirmed that introduction of the MDR-1 gene into stem cells protects these cells subsequently from large doses of taxol. This approach is now being appraised in patients receiving high-dose chemotherapy for a range of cancer types, including breast and ovarian cancer and brain tumours.

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