A potential new therapy for mesothelioma could come in the form of a cancer-targeting virus that selectively destroys cancer cells while sparing healthy cells. Triggering that virus to express the antiviral protein, interferon-beta, could further enhance the immune response against the cancer, and reduce the risk of treatment side effects, according to a study of mice published in the October 1 issue of Cancer Research.
The viruses used in the study are called oncolytic viruses, and their potential lies in their ability to specifically target cancer cells without harming healthy cells. “The viruses that we use have a preferential tropism for cancer cells over normal cells. That is, they replicate in mesothelioma cells much more potently than they do in normal cells,” explains lead author Richard Vile, PhD, Professor of Immunology and Richard M. Schulze Family Foundation Professor at the Mayo Clinic.
When normal, healthy cells come into contact with a virus, they respond by producing high levels of the antiviral protein, interferon. The interferon shuts down that cell, as well as neighboring cells, before the virus has a chance to replicate. “In contrast, many mesothelioma cells are defective in their response to interferon, so even though the virus infects them, those cells no longer shut down viral replication like normal cells do,” Dr. Vile explains. This means that, unlike chemotherapy drugs, which destroy cancerous and healthy cells alike, oncolytic viruses destroy cancer cells specifically and are less likely to trigger harmful side effects.
To target mesothelioma cells in the study, Dr. Vile and his colleagues used vesicular stomatitis virus (VSV), which is in the same virus family as rabies. The VSV they used was designed to express interferon-beta.
The researchers injected either VSV-expressing interferon-B or a control substance into mesothelioma tumors in mice. Tumors shrank significantly in mice that received the VSV treatment. Four of eight mice were cured of their tumors, compared with zero of eight mice in the control group. What’s more, all of the surviving mice rejected a later challenge when they were again injected with mesothelioma cells, indicating that the virus conferred long-term protection.
Triggering the virus to express interferon-beta enhanced the immune-stimulating activity involved in killing tumor cells, the researchers discovered. It also further protected healthy cells from the virus, preventing adverse side effects.
Dr. Vile cautions that the results of animal studies often do not translate into human benefits, but he says his team is pleased with the results thus far. “I think they give us an excellent platform to go into clinical trials and give us reason to believe that we will have an effect in human patients,” he says.
The next step in his research is to determine the best vector platform to target mesothelioma. This study used VSV, but Dr. Vile’s collaborator, Steven Albelda at the University of Pennsylvania, has been working with an adenovirus that also expresses interferon-beta. “One of our next preclinical steps is to see which platform is most effective in animals, and develop whichever one is clinically likely to be most potent,” Dr. Vile says.
Willmon CL, Saloura V, Fridlender ZG, Wongthida P, Diaz RM, Thompson J, Kottke T, Federspiel M, Barber G, Albelda SM, Vile RG. Expression of IFN-beta enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma. Cancer Res. 2009;69:7713-7720.