Virotherapy uses oncolytic, “cancer killing,” viruses to attack cancer cells.
Researchers are actively modifying existing viruses to make them more effective.
Virotherapy shows promising results when combined with other treatments.
Currently, virotherapy for mesothelioma is only available through clinical trials.
Oncolytic virotherapy is the use of viruses to target and destroy cancer cells. Collectively, the use of viruses to treat mesothelioma is known as mesothelioma virotherapy. Virotherapy is rapidly emerging as a safe and effective treatment option for people with malignant mesothelioma and other cancers.
What Is Virotherapy?
Virotherapy employs oncolytic viruses to selectively target and kill cancer cells (“onco” means cancer, “lytic” means to destroy, usually cells). For example, the rabies virus selectively targets nerve cells, and the hepatitis B virus selectively targets liver cells. Once an oncolytic virus has invaded the cancer cell, it may kill it in any number of ways. In this way, scientists are able to harness the power of a destructive natural force—oncolytic viruses—to fight cancers, such as mesothelioma.
Viruses and Cancer: Early Virotherapy
While virotherapy is among the very newest cancer treatments, the association between viral infection and cancer remission has been recognized for at least the last century. Numerous reports emerged of cancer patients who developed certain viral infections experienced a temporary remission of their cancer. Not surprisingly, researchers experimented with ways to actively infect patients with viruses in an effort to treat their cancers.
The first major clinical trial in oncolytic virotherapy came in 1949. Twenty-two people with Hodgkin’s disease were injected with hepatitis B virus taken directly from the blood and liver of people with active hepatitis B. Seven patients enjoyed a clinical remission and the tumors of four patients decreased in size. On the other hand, two-thirds of patients treated newly developed hepatitis B with all of its symptoms, and one study participant died.
Two seminal trials were held in the 1950s with similarly mixed results. Cancer entered remission in a small portion of patients, but many more encountered serious side effects or even died during the study. Perhaps the most successful of the early virotherapy studies came in 1974, when 90 people with advanced cancers were infected with live mumps virus. Thirty-seven people had complete or greater than 50% remission and only 11 patients did not respond to the virotherapy. Seven out of 90 had serious adverse reactions from the mumps virus, however. With these serious complications, limited successes, and the availability of the first chemotherapeutic drugs, the trials of oncolytic virotherapy in humans virtually stopped by the mid-1970s.
The New Age of Virotherapy
Prior to the 1970s, the viruses used to infect patients with cancer were natural, unmodified forms of the virus that could be found in nature. More specifically, they were extracted directly from patients with active viral infection. The fields of molecular biology, cancer biology, and virology have grown astronomically since the 1970s. Virologists are now able to isolate individual viruses or grow pure viruses in clean settings. Moreover, viruses can be attenuated to eliminate the severe symptoms of viral infection (e.g., as done in vaccine development) while achieving the desired, cancer-fighting effect. Indeed, the viruses used for modern oncolytic virotherapy are extremely well tolerated, even at very high dosages.
Another key factor that sets modern virotherapy apart from the trials of the 1950s is the use of combination virotherapy. In combination virotherapy, researchers attach a specific molecule such as a cytokine, hormone, or protein, to the virus. These attached molecules may enhance the effect of the virus in various ways, such as guiding the virus to the tumor or enabling the virus to enter tumor cells.
The ideal oncolytic virus would be able to accomplish all of the following:
- Seek out and infect all cancer cells in a person’s body;
- Destroy those cancer cells;
- Not infect healthy cells;
- Not cause serious symptoms of infection or disease.
Some viruses are naturally able to achieve some of these, but no single, naturally-occurring virus meets all of these criteria. However, researchers have developed certain strategies to take existing viruses and modify them to become closer to this ideal.
Adenovirus is an example of natural virus that has been adapted to become a more potent oncolytic virus. The genetic material of adenovirus can be easily manipulated, and it has been extensively modified and tested over several decades. Even in the virus’ natural form, adenovirus infections usually cause mild to moderate symptoms for a few days. In its modified form, however, oncolytic adenovirus is well-tolerated.
Virotherapy Treatment Process
Virotherapy specifically for the treatment of mesothelioma is currently only available as part of a clinical trial. Since mesothelioma virotherapy is an experimental therapy, patients usually must have advanced disease and failed to receive good or consistent benefit from approved therapies before they can be enrolled. Also, since the oncolytic virus is injected into the space between the chest wall and the lung (i.e., the pleural space), most candidates for mesothelioma virotherapy must also have some degree of pleural effusion around the tumor.
Mesothelioma virotherapy can be administered in various ways. In general, patients must undergo mesothelioma staging with radiological and histological studies. In order to track the effect of the oncolytic virus, specific measurements of the tumor may be taken (e.g., chest CT or MRI) prior to the treatment. These are compared to images taken after the virotherapy treatment is complete.
Tumor-specific promotors may be identified and used to make sure the oncolytic virus specifically targets mesothelioma cells and does not affect healthy cells. For example, researchers modified adenovirus so that it contained a tumor-specific promotor called survivin.12 This modification improved the adenovirus’ ability to infect mesothelioma cancer cells and kept it from infecting other cells. Other attachments to the virus, such as cytokines, may enhance the tumor-killed effect of the oncolytic virus.
Virotherapy and Other Experimental Treatments
Mesothelioma virotherapy may be even more effective when combined with other traditional and experimental therapies. Laboratory studies indicate that oncolytic viruses are more successful at killing mesothelioma cells when combined with cisplatin and pemetrexed, a standard malignant mesothelioma treatment.
Since viruses affect cancer cells directly and provoke the immune system, there is great potential to combine virotherapy with immunotherapy. Some modifications made to oncolytic viruses are, indeed, a form of immunotherapy. For example, when vaccinia virus was combined with the cytokine IL-2, the virus combination not only destroyed malignant mesothelioma cells from within, but also provoked a robust immune response against cancer cells, further destroying them.
Laboratory studies and early clinical trials are showing that the combination of virotherapy and viral immunotherapy is a potent combination, even in malignant mesothelioma cancer cells. Clinical trials are recruiting to test these combinations in patients.
Virotherapy Clinical Trials
To date, the main viruses used in mesothelioma virotherapy have been adenovirus, herpes simplex virus, measles virus, and vaccinia virus. About half of the 60 patients with malignant mesothelioma treated with various forms of oncolytic adenovirus have enjoyed a clinical response. Early trials with modified vaccinia virus showed the oncolytic virus was safe, but did not significantly disrupt mesothelioma cells. Trials of the modified vaccinia virus, GL-ONC1, an oncolytic measles virus (MV-NIS), and herpes simplex virus are ongoing.