This issue of Oncology features an excellent review of gene therapy for head and neck cancers. Lamont and colleagues have highlighted the principles of genetic intervention, the current state of available therapies, and the results of human trials in an organized and coherent manner.
Obstacles to Effective Gene Therapy
There have been many obstacles to the development of effective gene therapy in malignant disease. The first is finding appropriate molecular targets or cellular alterations that are widely prevalent in the tumor cell milieu and that give these cells a proliferation advantage. One must also find a means to preferentially transfect cancer cells while sparing normal tissue. This involves not only delivering the therapy to the tumor but also enabling the gene to produce the desired effect. In addition, the gene or vector must not be toxic to the host. Moreover, there is the threat that the host may ultimately reject the agent as a foreign protein.
Ideal Features for Gene Therapy in Head and Neck Cancer
Cancer of the head and neck offers certain advantages that help overcome some of the barriers to gene therapy mentioned in the article by Lamont et al. For example, tumors of the head and neck can often be directly visualized and accessed, thereby making intratumoral or topical therapy practical. Furthermore, molecular alterations—such as the p53 mutation, cyclin D1 amplification, and epidermal growth factor upregulation—commonly occur in head and neck cancer and are responsive to gene therapy strategies.
Immune evasion is another important mechanism of a cancer cell’s propagation, and head and neck cancer cells employ several strategies to ensure their survival, including downregulation of major histocompatability complex and co-stimulatory molecules, underexpression of death-signal receptors, and production of proapoptotic ligands against cytotoxic immune cells.
As detailed in the Lamont et al article, researchers have identified these features of head and neck cancer and have developed therapies to take advantage of them. A number of these therapies have shown merit in human trials, including adenovirus (Ad)-p53, Allovectin-7, herpes simplex virus-thymidine kinase (HSV-tk) strategies, and ONYX-015. Other approaches, however, also deserve mention.
Successful preclinical experiments have been carried out using cyclin D1,[6,7] Stat3, and vascular endothelial growth factor antisense transfection. Gene replacement has also been attempted with p21 adenoviral and retroviral vectors. Immunomodulation has been accomplished with the B7 co-stimulatory antigen and granulocyte-macrophage colony-stimulating factor (Leukine) gene transfer. Gene-directed enzyme prodrug therapy using a cytosine deaminase/fluorocytosine (CD/5-FC) system has yielded encouraging results in other malignancies.[14,15]
Nevertheless, although responses have been demonstrated, it is unlikely that any of these strategies alone will result in significant improvements in survival. The vectors currently being utilized will transfect only a minority of tumor cells with only moderate specificity. Furthermore, the therapies often require repeated administration, with prolonged and complete remissions rarely occurring. To combat these problems, researchers have undertaken several novel tactics.
The article by Lamont et al highlighted the results obtained at the M. D. Anderson Cancer Center using ONYX-015 in combination with cisplatin (Platinol) and fluorouracil. Adding gene therapy to established therapeutic modalities would appear to be a logical step toward improving efficacy. To that end, Rogulski et al combined ONYX-015 with radiotherapy in cell lines with intact and deficient p53. Results demonstrated a better effect with dual therapy, especially in cells with mutated p53.
p53 Gene Replacement Plus Radiotherapy
Since a p53 mutation often renders tumor cells resistant to radiotherapy, one would expect an added benefit of combining p53 gene replacement with radiotherapy. This has been demonstrated in a radioresistant head and neck cancer cell line xenograft murine model employing an adenoviral vector.
This same group was able to demonstrate greater tumor specificity and response using a transferrin ligand-targeted liposome p53 delivery system and radiotherapy. The transferrin ligand provided the system with the ability to almost exclusively and efficiently transfect tumor cells. Once the normally radioresistant cell line expressed wild-type p53, it underwent apoptosis in response to radiotherapy exposure.
Others have attempted to target the epidermal growth factor receptor,[19-21] integrins, and the fibroblast growth factor receptor—all of which are overexpressed in head and neck cancer—to improve transfection specificity and efficacy. In fact, a fibroblast growth factor-targeted adenovirus has been successfully utilized to transfect cell lines with HSV-tk and enhance survival upon ganciclovir (Cytovene) exposure. A "double suicide gene" approach has also been reported using an HSV-tk/ganciclovir and CD/5-FC system, thereby improving the effect of radiotherapy in cervical carcinoma xenografts.
Other Applications for Gene Therapy
Another application of gene therapy may be in the adjuvant or minimal-disease setting. The presence of p53 mutation has been linked to increased rates of locoregional failure following curative intent therapy. Lamont et al discussed the use of Ad-p53 as a surgical adjuvant in an attempt to lower this failure rate.
Moreover, our institution has employed ONYX-015 as a mouthwash preparation to treat clinically apparent premalignant lesions. We have been able to demonstrate regression of dysplasia in this condition and are working to understand the role of specific molecular alterations on the effect of ONYX-015.
One must also keep in mind the significant progress that has been made in newly developed chemoradiation protocols. Employing concurrent chemotherapy with dose-intense radiation schedules has shown a benefit in terms of local control and overall survival. These strategies need to be further advanced and more widely applied while newer therapies are pursued.
It is apparent that gene therapy is currently in its infancy and that many obstacles need to be overcome before this strategy becomes a cornerstone of our armamentarium. Nevertheless, major strides have been made in the last decade, and the pace of advancements is increasing dramatically.
It is conceivable that many of these genetic-based therapies will one day revolutionize the treatment of head and neck cancers. One can envision a future when gene therapy will be combined with conventional chemotherapy, radiation, surgery, and other novel therapeutics to enhance the outcome of this deforming and deadly disease.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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