Gene Therapy for Head and Neck Cancer

Mutagenic factors such as alcohol, tobacco and human papilloma virus (HPV) are causative factors in HNSCC. Despite advances in surgical techniques, chemotherapy and radiotherapy, a significant improvement in survival of HNSCC patients has not been seen.

Gene therapy can be defined as introduction of nucleic acids (usually DNA) into tissues for therapeutic effect. Because of their location, head and neck cancers are relatively accessible for DNA injection, making them ideal candidates for gene therapy.

For gene therapy to be effective, stable expression of the introduced genes must be achieved. This has been attempted by a variety of strategies: including naked DNA, liposome-DNA complexes, engineered viruses and DNA-coated tungsten particles. A number of gene therapy clinical trials for head and neck cancer have been completed and the findings are encouraging.

One of the most common mutations seen in human cancer cells is in the p53 gene. The normal function of this gene is to cause cells with damaged DNA to die (programmed cell death or apoptosis). When it is mutated, abnormal proliferation of cells and tumor formation occurs. A genetically engineered adenovirus has been used to transfer copies of the normal gene to HNSCC patients, in combination with chemotherapy or radiotherapy. Responses to the treatment were reported, but survival rates were not significantly better than patients treated with chemotherapy or radiotherapy alone.

Tumors need a blood supply to survive and spread. Endostatin is a protein that inhibits the formation of new blood vessels and can hinder tumor growth. Transfer of the gene coding for endostatin has been carried out in patients with HNSCC. In some cases the treatment appeared to halt progression of the disease. In light of these promising early results, further clinical trials are to be initiated.

Inhibition of genes that are essential for tumor survival can be achieved through the use of antisense DNA. One gene that has been targeted in this way is the EGFR gene which is amplified in more than 90% of HNSCC patients. When EGFR antisense DNA was injected into HNSCC tumors a clinical response was seen in 29% of patients.

HNSCC patients show deficiencies in many components of their immune system. In addition, HNSCC tumor cells possess mechanisms to avoid detection by the immune system. Immune gene therapy for head and neck cancer aims to introduce genes that send signals to the immune system, stimulating an anti-tumor immune response. MHC alloantigens (Allovectin-7) have been injected into 60 HNSCC patients. A single cycle of treatment resulted in 23% of the patients showing disease stability.

The Current State of Head and Neck Cancer Gene Therapy, S.Thomas & J.Grandi. Human Gene Therapy, 2009, Vol 20, P1565-1575

Targeted Genetic and Viral Therapy for Advanced Head and Neck Cancers, P.Huang, J.Chang, D.Kirn, T.Liu. Drug Discovery Today, 2009, Vol 14 P570-578