Suicide Gene Therapy

Modified E.Coli Used for Suicide Gene Therapy

In suicide gene therapy, doctors modify a virus or the E. coli bacterium (pictured) to safely deliver cancer-killing genes to mesothelioma tumors.

Suicide gene therapy is an experimental treatment option that shows great potential as a targeted therapy for mesothelioma, although it is currently available only through clinical trials.

Unlike some traditional cancer treatments that affect the whole body, targeted therapies treat mesothelioma by manipulating the specific molecules that control tumor growth and progression. As a result, suicide gene therapy and similar treatments are much less harmful to healthy cells.

One of several gene therapy techniques under research, suicide gene therapy forces cancer cells to self-destruct after they are injected with modified genetic material. While standard chemotherapy drugs damage both healthy and cancerous cells, suicide gene therapy delivers genes that transform initially harmless drugs into highly toxic ones, but only within tumor cells.

Researchers have completed suicide gene therapy trials for the treatment of several cancers, including glioma, prostate cancer, ovarian cancer and mesothelioma. Early-phase clinical trials have demonstrated promising evidence of tumor regression and extended survival, with moderate safety concerns.

Suicide gene therapy may be especially favorable for pleural mesothelioma patients because of several defining characteristics of the disease.

Defining Characteristics of Pleural Mesothelioma

  • A lack of effective therapies
  • Tumor structure promotes efficient gene transfer
  • Limited cancer spread during early stages
  • Easily accessible tumors

Improvements to suicide gene therapy are necessary to maximize gene transference, increase the bystander effect and to encourage anti-tumor immune responses – all complex biological processes that lead to a greater amount of cancer cell suicides. Future trials will concentrate on refining these processes to boost the effectiveness of this therapy.

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How Does Suicide Gene Therapy Work?

Chemotherapy

Suicide gene therapy accomplishes the same end goal of chemotherapy treatments, but by different means. While chemotherapy targets all of the body’s rapidly dividing cells with the intention of killing cancer cells, suicide gene therapy allows doctors to deliver a cancer-killing drug solely to mesothelioma tumors. This bypasses chemotherapy side effects like nausea and hair loss, which are caused by collateral damage to noncancerous cells.

To prompt cancerous cells to destroy themselves, doctors use a two-step process. First, they inject a genetically modified virus into the tumor site. The most widely used virus for the treatment is the herpes simplex virus, but the E. coli bacterium is also common. Altered so that it cannot make the patient sick, the virus deposits a gene into the cancer cells that causes them to produce a special enzyme. The most extensively studied genes that achieve this are called herpes simplex virus thymidine kinase (HSV-tk) and cytosine deaminase (CD).

Suicide Gene Therapy Process

Suicide gene therapy process

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Once the virus triggers production of the enzyme, doctors initiate step two by injecting the patient with a unique type of chemotherapy drug called a prodrug. Suicide gene therapy typically uses ganciclovir (GCV). When administered, GCV and other prodrugs are nontoxic, and thus cause no harm to healthy cells.

But when GCV comes in contact with the special enzyme, the prodrug turns highly toxic. This starts a natural biological process called programmed cell death, which causes cells to commit suicide. Because HSV-tk and CD are not present in any of the body’s healthy cells, the prodrug only destroys cancer cells that were genetically altered by the virus.

Although only a limited number of tumor cells will take in HSV-tk or CD from the virus, the activated prodrug is passed on to neighboring cells through what doctors call the bystander effect. Further, cells that destroy themselves as a response to treatment attract immune cells that clear the tumor site of dead and dying cancer cells.

Research and Clinical Trials

  • Researchers

    Two prominent researchers who paved the way for mesothelioma suicide gene therapy are Dr. Steven Albelda and Dr. Daniel Sterman. Albelda currently serves as the Director of Lung Research at the University of Pennsylvania, and Sterman is the Clinical Director of the Thoracic Oncology Gene Therapy Program at Cornell University.

  • HSV-tk Treatment

    Along with several associates, Albeda created a model demonstrating that HSV-tk could be used as an effective treatment for peritoneal mesothelioma in 1995. Their study led to the approval of gene therapy clinical trials. Four years later, Albelda and Sterman collaborated on the first report of the clinical uses of gene therapy for mesothelioma patients.

  • GCV

    In 1998, Sterman and colleagues evaluated patient tolerance of the HSV-tk gene and the prodrug GCV in a phase I clinical trial of 21 pleural mesothelioma patients. The gene was delivered by an adenovirus, which was given to the patients in an intrapleural injection. The trial confirmed the safety of the treatment, and 11 patients experienced successful gene transfer.

  • Animal Trial

    Multiple studies using laboratory mice have also demonstrated the benefits of suicide gene therapy for mesothelioma treatment. For example, one animal trial performed by Veldwijk and colleagues found that suicide gene therapy shrank tumors and extended survival by 144 days. Mesothelioma cell growth was also slowed, evidenced by a 39 day delay in doubling time. This measurement describes the time it takes for a tumor to double in size.

Obstacles

Researchers are determined to overcome some of the weaknesses of suicide gene therapy, such as a limited number of successful gene transfers. They call this low transduction efficiency, which means the cancer cells are not absorbing the virus-delivered genes efficiently enough.

Although the bystander effect compensates for this problem, improving the transfer of the activated chemotherapy drug to nearby cancer cells is suspected to enhance the clinical benefits of this therapy.

Also, while clinical trials have documented safe and non-toxic patient responses to suicide gene therapy, there have been occurrences of side effects, especially in the earlier trials. In one study, patients undergoing chemotherapy with GCV after doses of HSV-tk experienced side effects including anemia, fever, transient liver enzyme elevation, temporary inflammatory responses and bullous skin disorders. Controlling negative responses such as these is a primary goal of ongoing gene therapy research.

The Future of Suicide Gene Therapy

  • Combining Treatments

    The future of this field will center on combining suicide gene therapy with other treatments, improving the bystander effect and finding the optimal method for delivering GCV and the HSV-tk gene.

  • Bystander Effect

    Improvements to the bystander effect will be propelled by the integration of proteins known as cytokines. Sterman and Albelda have found a way to use one cytokine, interferon (IFN)-beta, to activate the immune system. They tested this cytokine on animals and found that one dose prolonged survival, which provided a foundation for future testing.

  • Added Benefits

    Sterman and DeLong suggest there are added benefits to repeated suicide gene therapies using GVC. When prodrugs in their toxic state are transferred to neighboring cells unaffected by viral gene transfer, they can trigger anti-tumor responses. This suggests that multiple treatments may promote tumor regression and extend survival. As a maximally-tolerated dose of the treatment has not yet been reached, higher doses are thought to be safe and effective, but must be investigated carefully.

  • Improving Treatment Safety

    Researchers also theorize that suicide gene therapy patients may benefit from debulking surgery before receiving the HSV-tk gene. Delivery of the gene after surgery is another potentially beneficial option, as well as direct injections of the HSV-tk gene into mesothelioma tumors.

    While suicide gene therapy has not yet been approved for widespread use by the U.S. Food and Drug Administration (FDA), clinical trials will explore ways to improve the safety and efficacy of the treatment, which may one day offer hope to patients with mesothelioma and various other cancers.

Additional Resources

  1. Albelda, S., Wiewrodt, R. & Zuckerman, J. (2000 April 18). Gene therapy for Lung Disease: Hype or hope? Annals of Internal Medicine, 132:8. Retrieved from: http://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&ved=0CDgQFjAB&url=http%3A%2F%2Fciteseerx.ist.psu.edu%2Fviewdoc%2Fdownload%3Fdoi%3D10.1.1.128.6660%26rep%3Drep1%26type%3Dpdf&ei=2h9iUN_WCYv7qAG7i4HIBA&usg=AFQjCNHhCF8PK7JsVBeLpWkuH0dOoDZ5mg
  2. Excerpt from Letter of Recommendation. (2010 November 17). Retrieved from: http://imig.org/wp-content/uploads/2010/02/Excerpt-from-Letter-of-Recommendation-for-Albelda.pdf
  3. Sterman, D., et al. (1998 May 1). Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma. Human Genome Therapy, 9:7. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/9607419
  4. Sterman, D., Kaiser, L. & Albelda S. (1999). Advances in the Treatment of Malignant Pleural Mesothelioma. Chest, 116. Retrieved from: http://chestjournal.chestjournal.chestpubs.org/data/Journals/CHEST/21930/504.pdf
  5. Sterman, D. & DeLong P. (2006). Therapy for Malignant Mesothelioma. Malignant Pleural Mesothelioma. New York: Oxford University Press.
  6. Yazawa, K., Fisher, W. & Brunicardi, F. (2002 April 15). Current progress in suicide gene therapy for cancer. World Journal of Surgery, 26:7. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/11948367
  7. Schwarzenberger, P., et al. (2011 September 9). Treatment of mesothelioma with gene-modified PA1STK and ganciclovir: a phase I study. Cancer Gene Therapy, 18:2. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/21904395
  8. Xia, W. (2008). Gene therapy for mesothelioma: studies of conditionally replicative adenoviruses and measles virus. Retrieved from: http://digital.library.adelaide.edu.au/dspace/bitstream/2440/50604/4/02chapters1-3.pdf
  9. Schwarzenberger, P., et al (1998 April). Gene therapy for malignant mesothelioma: a novel approach for an incurable cancer with increased incidence in Louisiana. Department of Medicine, 150:4. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/9610071
  10. Yang, J., Liu, T., Jiang, Y. & Lu, Y. (2012). ARTRA enhances the bystander effect of suicide gene therapy driven by the specific promoter LEP 503. Molecular Vision, 18. Retrieved from: http://www.molvis.org/molvis/v18/a216/mv-v18-a216-yang.pdf
  11. Vachani, A., Moon, E., Wakeam, E. & Albelda S. (2010 February 16). Gene Therapy for Mesothelioma and Lung Cancer. American Journal of Respiratory Cell and Molecular Biology, 10. Retrieved from: http://ajrcmb.atsjournals.org/content/early/2010/02/16/rcmb.2010-0026RT.full.pdf
  12. Hengge, U. (2008 February 20). Gene Therapy in Mesothelioma. Onkologie, 31:82. Retrieved from: http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ArtikelNr=117180&Ausgabe=235775&ProduktNr=224106&filename=117180.pdf
  13. National Cancer Institute. (2012). Targeted Cancer Therapies. Retrieved from: http://www.cancer.gov/cancertopics/factsheet/Therapy/targeted

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