Biomedical Engineering Reference
In-Depth Information
Table 14.6
Some specifi c cancer types for which human gene therapy
trials have been initiated
a
Breast cancer
Colorectal cancer
Malignant melanoma
Tumours of the central nervous system
Ovarian cancer
Renal cell carcinoma
Small-cell lung cancer
Non-small-cell lung cancer
a
Although several of the strategies listed in Table 14.5 are being employed in these
trials, many focus upon the introduction of various cytokines into the tumour cells
themselves in order to attract and enhance a tumour-specifi c immune response.
One of the earliest cancer gene therapy trials attempted involved the introduction of the TNF
gene into TILs. The rationale was that if, as expected, TIL cells reintroduced into the body could
infi ltrate the tumour, TNF synthesis would occur at the tumour site (where it is required). This
approach has since been broadened, by introducing genes coding for a range of immunostimu-
latory cytokines (e.g. IL-2, IL-4, IFN-
and GM-CSF) into TILs. A variation of this approach
involves the introduction of such cytokine genes directly into tumour cells themselves. It is hoped
that reintroduction of such cytokine-producing cells into the body will result in a swift and effec-
tive immune response, i.e. killing the tumour cells and vaccinating the patient against recurrent
γ
Box 14.2
Product case study: Gendicine
Gendicine is the tradename given to the fi rst gene-therapy-based medicine approved anywhere
in the world. It gained approval for use in the treatment of head and neck squamous cell car-
cinoma 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 prod-
uct 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 clarifi ed by fi ltration
and concentrated by ultrafi ltration. The product is then treated with a nuclease preparation in
order to degrade contaminant DNA and further downstream processing entails multi-step high-
resolution column chromatography (see also Figure 14.7).
Intratumoural injection is believed to facilitate vector uptake and expression of p53 in the adja-
cent tumour cell, leading to cell cycle arrest and apoptosis. Company data showed complete regres-
sion 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 adminis-
tered 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 compa-
nies, including Introgen Therapeutics (USA), whose p53 adenoviral-based drug Advexin has
entered phase III clinical trials for sqamous cell carcinoma in 2006.
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