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Gene Therapy for the Treatment of Oral Squamous Cell Carcinoma

¹ Departments of Otolaryngology and
² Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;

*corresponding author, The Eye and Ear Institute, Suite 500, 200 Lothrop Street, Pittsburgh, PA 15213, jgrandis{at}pitt.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION DEFINITION OF GENE THERAPY STRATEGIES FOR GENE THERAPY DELIVERY SYSTEMS GENE THERAPY STRATEGIES FOR... FUTURE DIRECTIONS REFERENCES

 
Despite advances in surgery, radiotherapy, and chemotherapy, the survival of patients with oral squamous cell carcinoma has not significantly improved over the past several decades. Treatment options for recurrent or refractory oral cancers are limited. Gene therapy for oral cancer is currently under investigation in clinical trials. The goal of cancer gene therapy is to introduce new genetic material into target cells without toxicity to non-target tissues. This review discusses the techniques used in cancer gene therapy for oral squamous cell carcinoma and summarizes the ongoing strategies that are being evaluated in clinical trials.

KEY WORDS: gene therapy • oral cancer • oral squamous cell carcinoma

	INTRODUCTION

TOP ABSTRACT INTRODUCTION DEFINITION OF GENE THERAPY STRATEGIES FOR GENE THERAPY DELIVERY SYSTEMS GENE THERAPY STRATEGIES FOR... FUTURE DIRECTIONS REFERENCES

 
Modifications of traditional cancer therapies, including surgery, radiotherapy, and chemotherapy, have not improved the survival rates of patients with mucosal squamous cell carcinoma. Local and/or regional tumor recurrence develops in approximately one-third of patients, despite definitive treatment (Schwartz et al., 2000). The patient with recurrent or metastastic cancer is often considered incurable. A variety of chemotherapeutic agents has been used alone, and in combination, for the treatment of recurrent oral squamous cell carcinoma. However, chemotherapy is associated with well-known toxicities and has demonstrated no clear impact on survival in patients with recurrent oral cancer (Schrijvers et al., 1998). Patients with recurrent oral cancer that is refractory to chemotherapy and/or radiation therapy have a median life expectancy of several months, and the response rate to second- or third-line chemotherapeutic regimens is approximately 15%. Two-thirds of patients dying of this disease have no evidence of symptomatic distant metastases. Therefore, local and regional disease control is paramount, underscoring an urgent need for more effective therapies. Gene therapy has the potential to target cancer cells while sparing normal tissues. Such a strategy may be useful for recurrent disease as well as in the adjuvant setting (i.e., at the resected tumor margins). However, the clinical application of gene therapy for treatment of oral cancer will require optimization of gene delivery in conjunction with determinations of transfection efficiency.

	DEFINITION OF GENE THERAPY

TOP ABSTRACT INTRODUCTION DEFINITION OF GENE THERAPY STRATEGIES FOR GENE THERAPY DELIVERY SYSTEMS GENE THERAPY STRATEGIES FOR... FUTURE DIRECTIONS REFERENCES

 
Gene therapy can be defined as gene transfer for the purpose of treating human disease (Cusack and Tanabe, 1998). This includes the transfer of new genetic material as well as the manipulation of existing genetic material. This holds true especially for cancer cells, where dominantly activated oncogenes can be targeted. The transfer of genetic material may occur in vivo (where the gene is introduced into the body) or ex vivo (where a tumor is removed, the genetic materials delivered, and the cells are then re-introduced into the patient). The ex vivo approach has not been utilized in oral cancer because superficial lesions usually lend themselves to the direct injection of genetic material.

	STRATEGIES FOR GENE THERAPY

TOP ABSTRACT INTRODUCTION DEFINITION OF GENE THERAPY STRATEGIES FOR GENE THERAPY DELIVERY SYSTEMS GENE THERAPY STRATEGIES FOR... FUTURE DIRECTIONS REFERENCES

 
Potential uses of gene therapy in oral cancer include the treatment of recurrent disease and adjuvant treatment—for example, at surgically resected margins. Localized distant metastatic disease is another potential target of gene therapy in patients with oral cancer. Although systemic administration is theoretically desirable to address metastatic disease, gene therapy has not yet been shown to be suitable for systemic delivery in cancer patients. Due to the requirement for direct injection, oral cancer is a particularly appropriate target, since most primary and recurrent lesions are accessible to injection.

There are several general strategies utilized in a gene therapy approach to cancer, including:

1. addition of a tumor-suppressor gene (gene addition therapy);
   
2. deletion of a defective tumor gene (gene excision therapy);
   
3. down-regulation of the expression of genes that stimulate tumor growth (antisense RNA);
   
4. enhancement of immune surveillance (immunotherapy);
   
5. activation of prodrugs that have a chemotherapeutic effect ("suicide" gene therapy);
   
6. introduction of viruses that destroy tumor cells as part of the replication cycle;
   
7. delivery of drug resistance gene(s) to normal tissue for protection from chemotherapy; and
   
8. introduction of genes to inhibit tumor angiogenesis.
   

	DELIVERY SYSTEMS

TOP ABSTRACT INTRODUCTION DEFINITION OF GENE THERAPY STRATEGIES FOR GENE THERAPY DELIVERY SYSTEMS GENE THERAPY STRATEGIES FOR... FUTURE DIRECTIONS REFERENCES

 
Genetic material can be transferred via a vector that is defined as the vehicle that is used to deliver the gene of interest. The ideal vector would transfer a precise amount of genetic material into each target cell, thereby allowing for expression of the gene product without causing toxicity. Chemical transfection introduces DNA by calcium phosphate, lipid, or protein complexes. Lipid vectors are generated by a combination of plasmid DNA and a lipid solution that result in the formation of a liposome. This fuses with the cell membranes of a variety of cell types, introducing the plasmid DNA into the cytoplasm and nucleus, where it is transiently expressed. Many carcinoma cells, including oral squamous cancer cells, express high levels of folate receptor. Linkage of DNA or DNA-lipid complexes to folate can specifically target cancer cells. Pre-clinical studies have demonstrated the potential utility of linking targeting moieties to the gene therapy construct (Hofland et al., 2002). The DNA can then be internalized via receptor-mediated endocytosis.

Physical transfection of genes can be accomplished by electroporation, microinjection, or use of ballistic particles. Electroporation therapy with intralesional bleomycin has been reported to be a technically simple outpatient technique where high-voltage electric impulses can be delivered into a neoplasm by transiently increasing cell membrane permeability to large molecules, including cytotoxic agents, thus causing localized progressive necrosis. Unlike many laser ablation methods, electroporation can treat bulky tumors (> 2 cm) with complete penetration. Clinical trials demonstrated that electroporation was safe and efficacious in 14 patients with squamous cell carcinoma (Allegretti and Panje, 2001). Particle bombardment has been studied to deliver genes to the oral mucosa in pre-clinical animal models. Although gene transfer to mucosa has shown anti-tumor effects, the limited transfection efficiency must be addressed prior to clinical application (Shillitoe et al., 1998; Wang et al., 2001).

Viruses in Cancer Gene Therapy
Viruses commonly used in cancer gene therapies include retroviruses, adenoviruses, and herpesviruses. Retroviruses are RNA viruses that undergo reverse transcription after infecting a cell, thereby producing double-stranded DNA. This DNA integrates in a stable, random fashion into the host genome, thus passing copies of the genes to all subsequent generations of cells. One limitation of retroviruses is that they can infect only actively dividing cells, leaving quiescent cells unaffected. The DNA is permanently inserted with such a strategy, thus raising long-term safety concerns. However, the limitation of retroviral infection has been overcome, in part, by the use of lentiviral vectors, which have been shown to activate the immune system in pre-clinical animal models of oral cancer (Cardinali et al., 1998; Pang et al., 2001).

Adenoviruses are DNA viruses that infect a cell, lose their protein coat, and transfer DNA into the nucleus, where it is transcribed. This DNA does not integrate into the host genome, and thus, its effects are transient (range: 7 to 42 days). Therefore, multiple administrations of the vector are usually required. The advantage of adenoviral vectors is that most cells are susceptible to infection, regardless of their position in the cell cycle. In addition, adenoviruses can be produced at a relatively higher titer, thus increasing the efficiency of their administration. Since exposure to adenovirus is common, approximately 90% of humans have already formed antibodies against the virus. Pre-existing antibodies can limit the effectiveness of this strategy, particularly upon a second exposure to the vector. Transduction studies have demonstrated that direct injection, but not topical application, of adenoviral constructs can transfect oral cancer cells in vivo (Clayman et al., 1995). Recently, a photochemical treatment was shown to enhance gene delivery by adenoviruses (Hogset et al., 2002). The majority of viral-mediated gene therapy trials in patients with oral cancer have used adenoviruses.

Most herpesvirus vectors are developed from strains of herpes simplex virus type 1 (HSV-1). This double-stranded DNA virus has several interesting properties, including the ability to remain latent in tissues and to be re-activated at the original site of infection. After infecting a cell, HSV-1 replicates within the cell, causing cell lysis and infection of surrounding cells. In addition, HSV-1 is a common pathogen in humans and rarely causes significant illnesses. HSV vectors can accommodate large pieces of foreign DNA and transfer genes rapidly and efficiently. A replication-conditional mutant of HSV has been shown to elicit anti-tumor responses in pre-clinical models of glioma and metastatic colon cancer (Endo et al., 2002; Toda et al., 2002). Adeno-associated viruses (AAV) have been explored in pre-clinical models as possible alternatives. AAV demonstrate low immunogenicity, have no known pathogenicity, target non-proliferating cells, and may have discrete genome insertion sites. "Suicide" gene therapy has been shown to be feasible in oral cancer cell lines with the use of an AAV vector (Fukui et al., 2001). AAV vectors have also been used successfully to transfer antisense or ribozyme genes in pre-clinical cancer models (Kunke et al., 2000).

Non-viral Vectors in Gene Therapy
Liposomes have no replication risk and are less immunogenic than viruses. Liposome-mediated gene transfer has been limited primarily by transfection efficiencies in vivo. Pegylated liposomes have been shown to localize to solid cancers and may deliver radiosensitizing agents preferentially to tumor tissue, potentially improving the therapeutic ratio of chemotherapy. A Phase I–II trial of pegylated liposome-encapsulated cisplatin (SPI-077) was conducted in 18 patients with treatment-naïve locally advanced, inoperable squamous cell cancer. Only two of 18 (11%) patients had partial responses to SPI-077, with two responses in 29 (6.9%) evaluable sites. SPI-077 was tolerated well, with no hematological, renal, hepatic, or neurological toxicities (Harrington et al., 2001).

The use of cationic liposomes as nonviral vehicles for the delivery of therapeutic molecules is becoming increasingly prevalent in the field of gene therapy. The transferrin ligand has been used to target a cationic liposome delivery system, resulting in a significant increase in the transfection efficiency of the complex (Xu et al., 1997). Delivery of wild-type (wt) p53 to a radiation-resistant squamous cell carcinoma cell line via this ligand-targeted liposome complex was also able to modulate the radiation-resistant phenotype of these cells in vitro. These results indicate that this tumor-specific, ligand-liposome delivery system for p53 gene therapy, when used in concert with conventional radiotherapy, may provide a new and more effective means of cancer treatment (Xu et al., 1999). The E1A adenovirus gene was delivered via intra-tumoral injection with liposomes in patients with recurrent head and neck cancer and was found to be safe in a Phase I trial (Yoo et al., 2001). Table 1 summarizes the advantages and disadvantages of the various clinically used vectors.

	GENE THERAPY STRATEGIES FOR ORAL CANCER

TOP ABSTRACT INTRODUCTION DEFINITION OF GENE THERAPY STRATEGIES FOR GENE THERAPY DELIVERY SYSTEMS GENE THERAPY STRATEGIES FOR... FUTURE DIRECTIONS REFERENCES

Antisense RNA and Ribozymes
Gene expression can usually be inhibited by RNA that is complementary to the strand of DNA expressing the gene. This "antisense" RNA can prevent the activity of several known oncogenes, including myc, fos, and ras, and can inhibit viruses such as HSV-1, HPV, and HTLV-1 (Wickstrom et al., 1988; Maeda et al., 1998). Such therapy can theoretically be directed toward carcinoma cells whose malignant phenotype is dependent upon the expression of particular oncogenes. Inhibition of expression of these oncogenes may alter the phenotype, thus abrogating tumor growth. Conventional antisense intervention has been limited by our inability to introduce sufficient quantities of antisense molecules to down-regulate the target gene and inhibit tumor growth. New strategies using strong promoters are being developed to address this potential limitation. We have developed an antisense approach to interference with an autocrine pathway in oral cancer involving the epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor alpha (TGF-). Pre-clinical studies using antisense sequences under the control of the U6 small nuclear RNA promoter demonstrated anti-tumor effects with minimal toxicity (He et al., 1998; Endo et al., 2000; Zeng et al., 2000). A Phase I study in patients with advanced oral cancer is under way to determine the safety and biologic effects of liposome-mediated intra-tumoral EGFR antisense gene therapy. The requirement for intralesional administration of antisense moieties raises concerns about the ability of such formulations to be delivered to the majority of tumor cells. Clinical trials using antisense oligonucleotides have used constant intravenous infusion, with limited toxicity and down-regulation of target gene reported (Waters et al., 2000). We have recently observed inhibition of tumor growth in xenograft models of oral cancer with systemic administration of EGFR antisense DNA (unpublished observations). The ability of gene-specific double-stranded RNA to trigger the degradation of homologous cellular RNAs is known as RNA interference (RNAi). Small interfering RNAs (siRNAs) mediate mRNA degradation in the process of RNAi and have been shown in recent studies to be potentially more effective than antisense RNA, likely due to enhanced resistance of siRNAs to nuclease degradation (Bertrand et al., 2002).

Immunotherapy
The immunologic gene therapy approach to oral cancer involves either increasing the immunogenic potential of tumor cells or augmenting the patient’s immune response to a tumor. Patients with squamous cell carcinoma of the head and neck demonstrate deficient function of several categories of immune cells, including natural killer cells, T-lymphocytes, and several cytokines (Gleich, 2000). Early attempts to enhance the immune response with bacillus Calmette-Guerin, either alone or in combination with methotrexate, demonstrated limited benefit (Papac et al., 1978; Taylor et al., 1983). Although oral cancer is not classically immunogenic, there is abundant evidence for immune recognition. Studies in pre-clinical animal models have included administration of interleukin-2 (IL-2)-activated lymphokine-activated killer (LAK) cells, tumor necrosis factor-alpha (TNF-), and immunomodulatory gene therapy with IL-2, IL-4, interferon-gamma (IFN-), IFN-, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, or IL-1ß transfected into tumors. The feasibility and efficacy of combination non-viral lipid-formulated murine interleukin 2 (mIL-2) and polymer-formulated murine interleukin 12 (mIL-12) gene therapy for squamous cell carcinoma have been investigated in pre-clinical models. The use of combined mIL-2 and mIL-12 gene therapy resulted in significant anti-tumor effects, most likely due to increased activation of cytolytic T-lymphocyte and natural killer cells (Li et al., 2001).

"Suicide" Gene Therapy
"Suicide" gene therapy involves the introduction of a gene into a cell that enables a prodrug to be activated into an active cytotoxic drug. The most extensively studied approach utilizes Herpes Simplex Virus-Thymidine Kinase (HSV-TK). This gene encodes a viral enzyme that phosphorylates ganciclovir into a monophosphate form, which is then further phosphorylated by intracellular enzymes into an active triphosphate compound that terminates DNA synthesis (Matthews and Boehme, 1988). Thus, this system selectively targets actively dividing cancer cells. Ganciclovir is also an excellent substrate for HSV-TK and a poor substrate for mammalian thymidine kinase, thereby making cytotoxic levels achievable in transfected cells, while leaving untreated cells relatively unharmed (O’Malley et al., 1996). Although the anti-tumor responses have been relatively poor in clinical trials, due to low transfection efficiencies, a high percentage of transfected cells does not appear to be required in vivo, due to the ability of transfected tumor cells to induce cell death in neighboring untransfected cells (bystander effect). Several mechanisms have been postulated to explain the induction of apoptosis in untransfected cells, including production of Fas/FasL, local inflammation, and devascularization (Floeth et al., 2001; Hall et al., 2002).

Replicating Viruses That Destroy Tumor Cells
A major obstacle to the development of effective suicide gene therapy strategies that rely on in situ transduction of tumor cells is the poor distribution of the vector throughout the tumor. The use of Ad.OW34, an E1B 55kD and HSV-TK-carrying, replication-competent adenoviral vector that has a wild-type adenovirus phenotype in replicating cells, has been evaluated in combination with ganciclovir (GCV) as a treatment for squamous cancer cell xenografts in nude mice and compared with that of a standard replication-deficient adenovirus expressing HSV-TK (Ad.TK). In this model, Ad.OW34 had significantly greater anti-tumor effects than did the traditional Ad.TK vector, administered alone or in combination with GCV. Interestingly, GCV did not further enhance the oncolytic efficacy of Ad.OW34. GCV also aborts viral replication and thus represents a fail-safe feature of this vector not found in wild-type adenovirus (Morris and Wildner, 2000).

A novel approach to gene therapy that has been extensively evaluated in pre-clinical and clinical studies for squamous cell carcinoma involves a vector that selectively replicates within and lyses tumor cells. An E1B 55kD gene-deleted adenovirus, ONYX-015 (d11520), has been developed for the treatment of tumors lacking p53 function (Heise et al., 1999). Since the E1B 55kD gene product is responsible for p53 binding and inactivation, it has been hypothesized that an E1B 55kD deletion mutant would be unable to inactivate p53 in normal cells and would thus be unable to replicate efficiently. In contrast, cancer cells lacking functional p53 (e.g., due to gene mutation) would hypothetically be sensitive to viral replication and subsequent cytopathic effects. Animal studies with ONYX-015 have also suggested that the efficacy of the virus is significantly augmented with the administration of standard chemotherapeutic agents. ONYX-015 can be safely administered via intra-tumoral injection to patients with recurrent/refractory squamous cell carcinoma. However, evidence of only modest anti-tumoral activity has been detected when this approach to gene therapy was used alone (Kirn et al., 1998; Nemunaitis et al., 2001). In a Phase II trial of a combination of intra-tumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck, there were substantial objective responses, including a high proportion of complete responses. By 6 mos, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction, although there was no apparent correlation between p53 mutational status in the tumor and clinical response (Khuri et al., 2000). These results suggest the lack of a bystander effect and underscore the importance of developing agents for systemic administration.

	FUTURE DIRECTIONS

TOP ABSTRACT INTRODUCTION DEFINITION OF GENE THERAPY STRATEGIES FOR GENE THERAPY DELIVERY SYSTEMS GENE THERAPY STRATEGIES FOR... FUTURE DIRECTIONS REFERENCES

 
Gene therapy represents a new and innovative approach to the treatment of cancer, including oral cancer. As our understanding of the molecular mechanisms of cancer increases, it is possible to exploit these principles and to target tumor cells selectively. Oral squamous cell carcinoma is an attractive tumor target due to its frequent genetic mutations and accessibility for intra-tumoral administration. Phase I trials have established the safety of gene therapy in squamous cell carcinoma of the head and neck, and Phase II studies have demonstrated clinical efficacy of gene therapy when combined with chemotherapy or radiation therapy. Phase III clinical trials and studies of the use of gene therapy in the adjuvant setting are presently under way. Further investigation is warranted to establish safe and effective approaches that utilize gene therapy for the prevention and treatment of oral cancer.

	REFERENCES

TOP ABSTRACT INTRODUCTION DEFINITION OF GENE THERAPY STRATEGIES FOR GENE THERAPY DELIVERY SYSTEMS GENE THERAPY STRATEGIES FOR... FUTURE DIRECTIONS REFERENCES

 
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