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In suicide gene therapy, doctors may modify a virus or bacterium, such as E. coli, to safely deliver a cancer-killing gene to mesothelioma cells.
Suicide Gene Therapy Facts
- Genetically modifies cancer cells with “suicide gene”
- Prodrug, which is a type of chemotherapy, then causes modified cancer cells to self-destruct
- Some trials for prostate cancer have shown positive results
- Only available through mesothelioma clinical trials
As one of several gene therapy techniques in development, suicide gene therapy forces cancer cells to self-destruct after they are injected with modified genetic material and a special type of drug. 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 conducted suicide gene therapy trials for several types of cancer, including glioma, prostate cancer, ovarian cancer and mesothelioma. In theory, suicide gene therapy could be especially favorable for the treatment of pleural mesothelioma, given the disease’s thin tumor structure, limited early-stage cancer spread and easily accessible tumors.
However, though some early-phase clinical trials have demonstrated promising evidence of tumor regression and extended survival, especially in prostate cancer, concerns remain about the safety and effectiveness of the technique for mesothelioma.
Improvements to suicide gene therapy are necessary to maximize gene transference, increase the bystander effect and encourage antitumor immune responses — all complex biological processes that lead to a greater number of cancer cell deaths. Ongoing clinical trials have concentrated on refining these processes to boost the effectiveness of this therapy.
How Does Suicide Gene Therapy Work?
Suicide gene therapy ultimately uses a drug to kill cancer cells, but unlike many forms of standard chemotherapy, it is a truly targeted approach.
The most common form of chemotherapy is systemic, meaning it affects all the rapidly dividing cells in the body. Systemic chemotherapy kills cancer cells but also causes collateral damage to noncancerous cells, leading to harsh side effects such as nausea and hair loss.
The objective of a targeted therapy is to kill cancer cells while leaving healthy cells unharmed. Suicide gene therapy is designed to accomplish this by ensuring the drug given to the patient only becomes toxic inside tumors.
To prompt cancer cells to destroy themselves, doctors use a two-step process.
Step 1: Vector Infects Cancer
First, doctors inject a microscopic DNA-delivery vehicle called a vector into the tumor site. The most widely used vector for this treatment is a genetically modified form of the herpes simplex virus, though other viruses, modified bacteria and even synthetic nanoparticles have all been tested for this purpose. No matter what it’s made of, the key to an effective vector is that it will target mesothelioma cells specifically.
When doctors use a virus, they first alter it so it cannot reproduce itself and make the patient sick. Instead of carrying its own DNA, the virus delivers a gene into 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).
Step 2: Prodrug Kills Cancer
Once the virus has implanted the suicide gene in the cancer cells, triggering enzyme production, doctors give the patient a unique type of chemotherapy called a prodrug. The prodrug is normally harmless, but when it comes into contact with the enzyme produced by the infected cancer cells, it starts a natural biological process called programmed cell death. Suicide gene therapy for mesothelioma typically uses a drug called ganciclovir (GCV).
The prodrug only becomes toxic in cancer cells genetically altered by the virus, thereby avoiding the side effects associated with systemic chemotherapy. However, because the virus never reproduces itself in the patient’s body, only a limited number of tumor cells receive the suicide gene.
The overall effectiveness of the treatment depends on gene transference to as many cancer cells as possible as well as two other complimentary effects:
- Bystander effect: When a cancer cell self-destructs, the activated prodrug inside it can be passed on to neighboring cells in the tumor. A powerful bystander effect allows a single infected cancer cell to kill itself and several more cancer cells around it.
- Immune system response: When cells undergo programmed cell death, they attract immune cells whose job it is to clear the body of dead and dying cells. If many cancer cells self-destruct at once, it may provoke a beneficial immune system response against the whole tumor, as in immunotherapy.
Development of Suicide Gene Therapy for Mesothelioma
Albelda currently serves as the director of lung research at the University of Pennsylvania School of Medicine, and Sterman is the director of the multidisciplinary pulmonary oncology program at the New York University Langone Medical Center.
Along with several associates, Albeda created a model demonstrating 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.
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.
Researchers are also experimenting with suicide genes to improve the safety of gene therapies such as anti-mesothelin CAR T-cell therapy. In 2021, scientists outlined the benefits of including a suicide gene “kill switch” in their therapy which would deactivate the gene if toxicity became too high.
Future Directions for Research
Researchers are determined to overcome the current weaknesses of suicide gene therapy. The central challenge is low transduction efficiency, meaning cancer cells do not absorb the virus-delivered genes efficiently enough.
Improvements to the bystander effect may be propelled by the integration of proteins known as cytokines. Sterman and Albelda found a way to use one cytokine, interferon (IFN)-beta, to activate the immune system and prolonged survival in animal test subjects, providing a foundation for future testing.
Researchers also theorize suicide gene therapy patients may benefit from receiving the HSV-tk gene after tumor-removing surgery as a multimodal treatment approach.
In addition, while clinical trials have documented safe and nontoxic patient responses to suicide gene therapy, there have also been occurrences of side effects. In one study, patients undergoing chemotherapy with GCV after doses of HSV-tk experienced 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.
While the U.S. Food and Drug Administration (FDA) hasn’t yet approved suicide gene therapy for widespread use, clinical trials continue to explore ways to improve the safety and efficacy of the treatment.
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