Molecular Genetics of Head and Neck Cancer

Lyon L. Gleich, MD, Frank N. Salamone, MD


Cancer Control. 2002;9(5) 

In This Article

Gene Therapy

The goal of gene therapy for cancer is to introduce genetic material into malignant cells to cause tumor regression. Once introduced, these genes may directly replace the function of a mutated gene, convert prodrugs into antineoplastic compounds, or induce other mechanisms that lead to cancer cell death.

Vectors are the means by which genes are delivered to the cell. Viral and nonviral vectors (eg, adenovirus, retrovirus, and liposomal) are used. Despite the high transfection efficiency of some vectors, delivery to all tumor cells is not technically feasible.

Replacing a mutated p53 gene with a wild-type (normal) p53 gene is a potential approach to head and neck cancer treatment. This approach is limited by the lack of mutated p53 in many tumors and also by the current limitations of vector technology in delivering the gene. In a study of 17 patients with advanced recurrent or refractory unresectable head and neck cancer, treatment with delivery of the p53 gene using an adenoviral vector found only 2 patients with tumor regression of more than 50%.[97] An additional 17 patients with resectable disease were treated, and 2 remained disease-free for longer than 2 years.

ONYX-015 is an adenovirus from which the E1B region has been deleted. E1B inactivates p53, thereby allowing virus replication. Consequently, ONYX-015 should be able to replicate only in cells lacking functional p53 and thus potentially target cancer cells. Some conflicting data have emerged regarding the specificity of ONYX-015, although its proponents claim that the most stringent tests, ie, those comparing cell lines differing only in p53 status,validate the efficacy of ONYX-015.[98]

ONYX-015 was intratumorally injected in 22 patients with recurrent refractory head and neck cancer that had abnormal p53 immunochemistry.[99] A partial response was seen in 3 patients, and 2 had a minor response. A study involving 40 patients showed a partial response in 14%.[100] In another report, ONYX-015 was given in combination with cisplatin and 5-fluorouracil to treat 37 patients with recurrent head and neck cancer.[101] A partial response was seen in 15 patients. However, this was not a randomized trial, and it is not possible to conclude the true efficacy of ONYX-015 and chemotherapy combinations.

Head and neck cancer commonly has reduced MHC expression. MHC antigens can incite a vigorous immune response. A potential application in treating head and neck cancer is the use of gene therapy to deliver a class I MHC. If the MHC is human but foreign to the patient, it can induce an antitumor response either by presenting tumor antigens or by itself being an antigen. Allovectin-7 is a gene therapy product that uses a liposomal vector and encodes the class I MHC HLA-B7. A study of recurrent, advanced, unresectable head and neck cancer included 18 patients, all of whom were HLA-B7-negative. Patients received intratumoral injection of a gene transfer product (Allovectin-7), which resulted in complete or partial response in 4 patients.[102] A multi-institutional study, also of advanced unresectable head and neck cancer, included 60 patients who were HLA-B7-negative. After the first cycle of treatment, 23 patients had stable disease or a partial response and proceeded to the second cycle. After the second cycle and 16 weeks after the initiation of gene therapy, 6 patients had stable disease, 4 had a partial response, and 1 had a complete response.[103]

The tumor suppressor genes p16, p21, and Rb are frequently mutated in head and neck cancer and therefore are potential gene therapy targets. Studies in animal models support the potential for these genes in head and neck cancer therapy,[104,105] but the application of vector technology is currently limited, as seen with p53 gene therapy.


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