Principles of gene therapy

Several strategies have been developed that involve the insertion of genetic material into cancer cells or immune cells involved in tumour cell kill. The success of these approaches depends on the ability to deliver the genetic material to the target cells. The transfer of genetic material to a cell is termed ' transduction' and the delivery systems used to transfer genes to target cells are called 'vectors'. Transduc-tion of adequate amounts of genetic material into tumour cells represents one of the most challenging areas of gene therapy, and vector technology is one of the most important areas of current research.

For a vector to be practical for everyday clinical use, it must be:

1 Easy to manufacture

2 Specific to tumour cells or host cells that may benefit from modification

3 Efficient at transducing genetic material

4 Able to cause expression of the transduced gene for a sufficient period of time to be effective

5 Non-immunogenic, so it is not destroyed by the host's immune system

Table 21.1. Gene therapy vectors





• Integrate into target cell

• Require rapidly dividing


DNA, causing prolonged

cells (breast and ovarian

RNA viruses

gene expression

tumours may be indolent)

• Small host immune

• May cause mutations in


normal cells

• Specific for dividing cells

• Easy to manufacture


• Highly efficient at gene

• Cause a host immune


transduction into target


DNA virus


• Can be toxic to the host

• Can transduce a cell at any

• Lack target cell specificity

stage of cell cycle

(newer conditionally

• Very easy to manufacture

replicative adenoviruses

at high titres

are more specific)

• Transient expression of

transduced gene


• No immune response

• Relatively inefficient at

Positively charged

• Easy to manufacture

gene transduction

lipid membrane

• Can carry large amounts of

• No target cell specificity

complex surrounding

genetic material

• Transient expression of


transduced genes

Molecular conjugate

• Highly specific delivery of

• Difficult to manufacture

A protein/DNA

genetic material to target

• Transient expression of



transduced genes

• Can carry large amounts of

genetic material

Naked DNA

• Simple

• Can only be used where

Direct injection or

• No immune response

tumour cells can be easily

bombardment of

• Targeted


target cells with

• Unable to transduce a large


number of cells

Unfortunately, the perfect vector still does not exist, leading to severe limitations on current gene therapy strategies. As there is no vector that is clearly superior, the choice depends on the amount of genetic material to be transferred, the length of time the foreign gene needs to be expressed and the route of vector delivery (Table 21.1).

Once a vector has been developed and adapted to carry a therapeutic gene, the next stage is its delivery to the target cell or organ. In the treatment of breast or ovarian cancer, three main strategies are used: (1) local delivery, (2) systemic delivery, and (3) in vitro delivery.

Local delivery

For ovarian cancer, intraperitoneal injection of the vector is often the preferred approach. This allows the vector to be in direct contact with tumour deposits at a relatively high concentration and results in less immunogenicity than systemic approaches. Local delivery increases the efficacy of gene transfer and reduces the exposure of normal cells to the treatment. However, the vector will not enter tumour cells outside the peritoneal cavity and therefore this approach is less effective for widespread metastatic disease. The vector is also unlikely to penetrate bulky peritoneal disease.

In breast cancer, direct injection of vector into a tumour may be possible as this can also result in a high local concentration. However, metastatic disease, including local lymph node involvement, may not be adequately treated by this approach.

Systemic delivery

Systemic delivery has the advantage of treating both primary and metastatic disease. Potential difficulties may arise with a host immune response, resulting in the vector becoming ineffective or adding to its toxicity. There is also a danger of introducing foreign genetic material into normal cells. Newer developments of conditionally replicative viral vectors and the use of antibodies to target vectors to cell receptors or other surface antigens may, in the future, make systemic gene therapy more specific to cancer cells.

In vitro delivery

In this method the aim is to beneficially alter normal host cells (typically cytotoxic T-cells) by gene therapy ex-vivo in the laboratory. The modified cells are then reintroduced systemically to the patient. This procedure allows great flexibility in the manipulation of target cells and is very specific. However, cells for this have important biological requirements to be maintained during processing, making it very labour intensive and expensive. It also cannot be used to directly target cancer cells.

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