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. 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 natural power of oncolytic viruses to fight cancers, such as with mesothelioma patients.
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.
Early Timeline of Virotherapy
1949: First major clinical trial in oncolytic virotherapy
- 22 people with Hodgkin’s disease were injected with active hepatitis B virus
- 7 patients experienced remission
- 4 patients experienced decreased tumor size
1950s: Two seminal trials were held
- Mixed results were found, very similar to the earlier study
- Some patients did experience remission, but in small numbers
- Other patients had serious side effects, and some even died
1974: Successful cancer and virotherapy study
- 90 people with advanced cancers were infected with a live mumps virus
- 37 people had complete or greater than 50% remission
- 11 patients with no response and 7 patients with serious reactions
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
Typical Requirements for Virotherapy Candidates
- As an experimental therapy, patients usually must be in the advanced stages or have seen poor response to other therapies.
- Most mesothelioma candidates have pleural effusion, as the oncolytic virus is injected into the space between the chest wall and the lung (pleural space).
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 chemotherapy drugs cisplatin and pemetrexed, a standard malignant pleural 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), herpes simplex virus and other prospective viruses are on-going. Continued cancer research into newer treatments such as immunotherapy, gene therapy and oncolytic viral therapy offer hope towards finding a cure.