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Close but no cigar

Despite failure to show clinical benefit, gene therapy continues to offer hope for cancer treatment

DNA The advent of recombinant DNA technology led to the notion that foreign genes could be used to correct genetic defects and disease phenotypes and, with the development of retroviral vectors in the 1980s, it became a widely-accepted approach in treating human diseases, albeit one that has yet to be proven effective.

The Center for Biologics Evaluation and Research of the Food and Drug Administration (FDA) regulates human gene therapy products in the US and, as gene therapy experimentation raises many safety and ethical issues, it must be evaluated cautiously. Some of the field's darkest moments include the case of Jesse Gelsinger, who died in 1999 from massive organ failure after receiving a high dose of an adenoviral gene therapy for the treatment of ornithine transcarbamylase deficiency at the University of Pennsylvania. As a result, regulatory bodies such as the FDA and European Medicines Agency (EMEA) continue to reappraise the current framework and structure of gene therapy research and re-examine informed consent procedures.

Despite significant risks, many pharmaceutical companies have chosen to develop gene therapies as treatments for the most prevalent disease affecting society today – cancer. A number of promising candidates include Introgen's contusugene ladenovec (ADVEXIN), an adenoviral p53 gene therapy, and Ark Therapeutics' sitimagene ceradenovec (Cerepro). Both are being reviewed by the EMEA for the treatment of head and neck cancer and glioma, respectively.

Focus on cancer
As a leading cause of death worldwide, cancer is a popular area for the development of new and unconventional therapies, such as gene therapy. The concept of gene therapy follows from the idea that certain diseases are caused by the inheritance of a single, functionally-defective gene. Cancer is often associated with numerous gene mutations but, nevertheless, it has been widely chosen as a target for gene therapies.

Techniques used include substituting missing or altered genes to restore function (eg TNFerade, GenVec) and immunomodulation to stimulate the body's natural ability to attack cancer cells or to improve the sensitivity of cancer cells to chemotherapy (eg Allovectin-7, Vical). Gene therapies can be designed for administration as a monotherapy, or combined with conventional treatments to enhance therapeutic effects.

Significant risks are involved in changing an organism's genetic makeup, including insertional mutagenesis, which occurred in a gene therapy trial in 2003, using a retroviral therapy against X-linked severe combined immune deficiency disorder. Haematopoietic stem cells were transduced with a corrective transgene, which led to the development of T-cell leukaemia in some patients. These significant factors and problems such as the short-lived nature of gene therapy and the risk involved in using viral vectors may only be solved through additional research. Compounds that have had success, without the risk of adverse reactions, include contusugene ladenovec (ADVEXIN) and sitimagene ceradenovec (Cerepro).

Gene therapy effecacy
A logical path to test the effectiveness of gene therapy would be to identify cancer states caused by a known monogenic effect. The p53 tumour suppressor gene is deleted or mutated in many tumour cells and is one of the most frequently-mutated genes in human tumours. Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder that increases an individual's susceptibility to cancer. It is linked to germline mutations in the p53 tumour suppressor gene. Contusugene ladenovec (ADVEXIN), developed by Introgen and Gendux, combines a p53 tumour suppressor with a non-replicating, non-integrating adenoviral delivery system, for the treatment of head and neck cancer and LFS.

The US FDA recently notified Introgen that its Biologics Licence Application (BLA) for ADVEXIN for the treatment of head and neck cancer was not sufficiently complete. Statistical analyses based on data from the pivotal phase III trial comparing the length of survival of patients receiving ADVEXIN or methotrexate showed that patients with p53 tumour profiles positive for ADVEXIN efficacy demonstrated increased survival benefit at six months and overall following treatment. Patients with p53 tumour profiles negative for ADVEXIN efficacy also showed significantly increased survival benefit associated with methotrexate treatment. The gene therapy had similar overall survival to methotrexate in patients with p53 favourable and p53 unfavourable profiles (median survival 6.1 vs 4.4 months). Biomarker analyses showed that there was a significant correlation between an abnormal p53 biomarker and tumour response to contusugene ladenovec therapy, with the abnormal expression correlating to increased survival and tumour responses.

Viral gene therapy approaches are associated with a number of well-known limitations, like the unwanted immune responses seen in the case of Jesse Gelsinger. However, adverse events have not been a concern for ADVEXIN and Cerepro, another adenoviral vector-based therapy.

The FDA's refusal may have been based on ADVEXIN's failure to improve survival compared to conventional treatment, as the FDA previously suggested that data from a biomarker analysis would be acceptable.

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ADVEXIN is currently available on a compassionate use basis to eligible LFS patients under a protocol authorised by the FDA. Gendux previously applied for marketing authorisation in the EU for the treatment of LFS; however, this was withdrawn in January 2009 due to the company's marketing strategy. It is now under consideration for the treatment of head and neck cancer in the EU. Introgen intends to appeal the decision made by the FDA to reject ADVEXIN, as it is the company's lead candidate. It is assumed that it will be a difficult fight to the end. To date, neither the FDA nor EMEA have approved a gene therapy for use outside a clinical trial.

Another candidate under regulatory review is sitimagene ceradenovec (Cerepro), being developed by Ark Therapeutics for the treatment of high-grade glioma. It consists of the herpes simplex virus gene for thymidine kinase encased in an adenoviral vector in which the E1 and part of the E3 regions have been deleted to prevent replication. Following surgical removal of the glioma, sitimagene ceradenovec is administered by injection into the walls of the cavity, where it transfects normal brain cells with the thymidine kinase gene. Five days after surgery, ganciclovir is given intravenously. By this time, the tissue surrounding the resection site is expressing thymidine kinase, which converts ganciclovir to ganciclovir triphosphate, a compound that kills dividing cells via inhibition of DNA synthesis. Results from four clinical trials were used to support an application for marketing approval in the EU. Ark had previously submitted for early approval in October 2005 under "exceptional circumstances", allowing phase II data to be used; however, the EMEA concluded there was insufficient evidence to prove clinical benefit beyond doubt. Latest results from the phase III 904 study, reported in April 2009, showed increasing support for improved overall survival in patients receiving Cerepro plus standard care for the treatment of malignant glioma, compared with patients receiving standard care alone (either surgery and radiotherapy or surgery and radiotherapy plus temozolomide). An interim analysis in July 2008 showed a 42-day improvement in median survival (310 days vs 268 days) in patients receiving Cerepro and temozolomide and showed a significant improvement over standard care at 14 months. Cerepro is available to patients under exceptional circumstances in France. Ark Therapeutics seems confident enough in the product to pursue only one indication, and has smartly decided to postpone development of Cerepro for paediatric use until marketing authorisation has been obtained for use in adult patients.

In addition, GenVec is developing TNFerade, an adenovector which delivers the tumour necrosis factor alpha gene to cancer cells, currently in the phase III portion of a phase II/III trial for the treatment of pancreatic cancer. An interim analysis has shown an approximately 25 per cent lower risk of death in patients receiving TNFerade plus standard of care, compared with standard of care alone. These results seemed promising, however, at 24 months, overall survival was 10.6 and 11.3, respectively, with a median survival of 9.9 months for both study arms. The FDA informed the company that a benefit in overall survival can be considered as a basis for full regulatory approval of TNFerade. Whether this is shown in the latest trial remains to be seen; the next analysis is expected in late 2009.

TNFerade has also shown potential in the treatment of rectal cancer, head and neck cancer, metastatic melanoma and oesophageal cancer.

Velimogene aliplasmid (Allovectin-7) is a plasmid/lipid complex containing the DNA sequences encoding HLA-B7 and ß2 microglobulin, which together form a Class I Major Histocompatibility Complex (MHC-I antigen), being developed by Vical for the treatment of malignant melanoma. Intratumoural injection of velimogene aliplasmid leads to expression of HLA B-7 and ß2 microglobulin on tumour cells, leading to a corresponding enhancement of tumour antigen presentation, and a cellular immune response. Allovectin-7 is currently being evaluated in a phase III trial in malignant melanoma, and although no results have yet been reported from this trial, data from a phase II trial showed that 4 of the 15 responders receiving the 2mg high dose had a complete response and 11 had partial responses.

Ongoing research
The concept of gene therapy was fortunate enough to be medically and socially accepted before it was able to provide proven clinical benefits, and regulatory hurdles have not hindered the progress of research. Several ways to treat cancer using gene therapy have been discovered, including the enhancement of an individual's existing healthy cells to fight cancerous cells, destroying them or preventing their proliferation.

The constant interest in developing drugs to treat cancer, combined with an ever-increasing knowledge of the human genome provides justification for continued research in this field of personalised medicine.

The Author
Pipeline was written by Chin-Hang Kong of R&D Insight, using data derived from Adis Clinical Trials Insight and R&D Insight
To comment on this article, email

10th June 2009


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