Gene therapy and cancer

To date, the majority of gene therapy trials undertaken aim to cure not inherited genetic defects, but cancer. The average annual incidence of cancer reported in the USA alone stands at approximately 1.4 million cases. Survival rates attained by pursuit of conventional therapeutic strategies (surgery, chemo/radiotherapy) stand at about 50 per cent.

Initial gene therapy trials aimed at treating/curing cancer began in 1991. Various strategic approaches have since been developed in this regard (Table 14.5). Numerous trials aimed at assessing the application of gene therapy for the treatment of a wide variety of cancer types are now underway (Table 14.6).

Although many of the results generated to date provide hope for the future, gene therapy thus far has failed to provide a definitive cure for cancer. The lack of success is likely due to a number of factors, including:

• A requirement for improved, more target-specific vector systems.

• A requirement for a better understanding of how cancer cells evade the normal immune response.

• For ethical reasons, most patients treated to date were suffering from advanced and widespread terminal cancer (i.e. little/no hope of survival if treated using conventional therapies). Cancers at earlier stages of development will probably prove to be more responsive to gene therapy.

Table 14.5 Some therapeutic strategies being pursued in an attempt to treat cancer using a gene therapy approach. Refer to text for details

Modifying lymphocytes in order to enhance their anti-tumour activity Modifying tumour cells to enhance their immunogenicity Inserting tumour suppressor genes into tumour cells

Inserting toxin genes in tumour cells in order to promote tumour cell destruction Inserting suicide genes into tumour cells

Inserting genes, such as a multiple drug resistance (mrd) gene, into stem cells to protect them from chemotherapy-induced damaged Counteracting the expression of oncogenes in tumour cells by inserting an appropriate antisense gene

Table 14.6 Some specific cancer types for which human gene therapy trials have been initiated3

Breast cancer Malignant melanoma Ovarian cancer Small-cell lung cancer

Colorectal cancer

Tumours of the central nervous system Renal cell carcinoma Non-small-cell lung cancer

"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-specific 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 infiltrate 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-y 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 effective immune response, i.e. killing the tumour cells and vaccinating the patient against recurrent

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