Gene therapy is a promising treatment for mesothelioma, but it has been slow to make its way into clinical use because delivering enough therapeutic genes to effectively kill large numbers of cancer cells has proved challenging. Recently, mesothelioma researchers have been focusing on a method called immuno-gene therapy, which transfers just enough genetic material to trigger the patient’s own immune system to fight the cancer, according to a recent review published in the American Journal of Respiratory Cell and Molecular Biology.
Researchers have been investigating the use of gene therapy – introducing a gene or genes into the body that kill cancer cells or make those cells more sensitive to the effects of anticancer drugs – for approximately two decades. According to the review, mesothelioma is a particularly good target for gene therapy, because no treatment used so far (surgery, chemotherapy, radiation) has been able to effectively treat the disease, and because mesothelioma tumors tend to stay in one place until the late stages of the disease—making them good targets.
For a gene to be introduced into the body to kill mesothelioma or another cancer, it needs a vehicle—or vector—to help it reach the tumor cells. Gene therapy for mesothelioma can be administered using viruses (most commonly adenoviruses that have been altered in a lab so that they are unable to replicate), and coated DNA. Yet both methods have their limitations.
“The problem with viruses is that the body rejects the infectious cells very quickly,” explains the review’s author, Steven M. Albelda, MD, Professor of Medicine at the University of Pennsylvania School of Medicine, and Vice Chief of the Pulmonary, Allergy, and Critical Care Division. “The problem with coated DNA is that it’s very inefficient. The technology hasn’t really been able to infect the majority of tumor cells.”
When either viruses or DNA is injected by vein (which is how most drugs are administered), only a small amount of the vector actually reaches the mesothelioma cells. “The small amount that gets there doesn’t express the gene for very long,” Dr. Albelda says. When gene therapies are unable to reach large numbers of cancer cells, they need a strong “bystander effect,” which means that the cancer cells affected by treatment send out signals that also kill neighboring cells.
Given the challenges in reaching large numbers of mesothelioma cells, the focus of gene therapy has shifted to inciting the body’s own immune response against the cancer. The idea behind immuno-gene therapy is to inject just enough of the gene—for example, using a vaccine or cytokines (chemical messengers released by the immune system)—to stimulate an immune response powerful enough to trigger a strong bystander effect. “Now you’re just using the gene therapy to trigger the immune system, and most of the killing will be done by the body’s own immune system,” Dr. Albelda says.
Treatments that stimulate the patient’s immune system can be administered in two ways. One method is to create an off-the-shelf drug that can be injected into any patient. The other is to develop a highly personalized therapy using cells (such as dendritic cells or lymphocytes) taken from the patient’s own body. Those cells are then altered in a lab so that once injected back into the patient, they will attack mesothelioma cells.
Even immuno-gene therapy is limited in its ability to destroy large tumors such as advanced mesothelioma, which is why researchers are investigating combination approaches that pair up traditional therapies such as surgery and chemotherapy with immunotherapy. When researchers administer gene therapy after chemotherapy, the combination may heighten the response against the cancer.
“The other thing we’ve been working on which works really nicely is combining immunotherapy with surgery,” Dr. Albelda says. “The problem with surgery is it always leaves some cells behind. Our idea is that if we induce an immune response and we get rid of 95 percent of cancer cells with surgery, the immune system can clean up the remaining cells.”
The question that remains is how best to incorporate these therapies. “I think we have to learn how to integrate immuno-gene therapy with chemotherapy, radiation, and surgery in the right way,” says Dr. Albelda. As study results continue to improve, researchers are going to be able to initiate combination therapies earlier and earlier in the course of the disease, making these treatments more likely to be effective in mesothelioma in the future.
——————————————————————————————————— The University of Pennsylvania is developing a number of experimental clinical trial programs for malignant pleural mesothelioma, including gene therapy. The next clinical trial will evaluate two different chemotherapy regimens in combination with intrapleural adenoviral-mediated interferon-alpha gene transfer.
For more information regarding this and other clinical trials at the University of Pennsylvania, contact Adri Recio, RN at 215-573-6760 or email: arecio(at)mail.med.upenn.edu
Source: Vachani A, Moon E, Wakeam E, Albelda SM. Gene therapy for mesothelioma and lung cancer. Am J. Respir Cell Mol Biol. 2010. 42:1-9.