Researchers around the world are in the early stages of exploring an exciting treatment for mesothelioma called oncolytic virotherapy that uses viruses altered in the laboratory to find and destroy cancer cells without harming healthy cells. Also called oncolytic virus therapy and viral therapy, it targets specific receptors expressed by cancer cells that let the viruses in. Once the virus infects the cell, it either kills it or weakens it to make it more receptive to anti-cancer drugs. Virotherapy can be effective against numerous kinds of malignancies, including mesothelioma.
What Is Oncolytic Virotherapy?
Oncolytic virotherapy is a medical technology that researchers first began exploring in the 1950s. While investigating whether any viruses would be capable of killing cancer cells, they set out to see whether viruses could be selectively adapted for this purpose. These initial attempts were unsuccessful, as viruses that successfully killed malignant cells also had toxic impacts on normal cells and tissues.[1]
The protocol was reinvigorated by the development of recombinant DNA technology in the 1990s. Once scientists were able to manipulate the DNA of viruses, they began to develop viruses that were specifically adapted to kill tumor cells and leave normal cells alone. The first genetically modified virus was a herpes simplex virus that was used to treat the rare and deadly form of brain cancer known as glioblastoma. The virus underwent deletion of a gene encoded by herpes simplex that allows it to replicate in non-dividing cells but not in dividing cells. Without that specific gene, the virus replicated in the rapidly dividing glioblastoma cells but left healthy cells alone.[1]
When altered viruses infect cancer cells they’ve been reprogrammed to target; the infected cells begin to deteriorate in a process known as oncolysis. The oncolytic virus multiplies and infects its neighboring cells, destroying them, too, while at the same time, debris and antigens released from these deteriorating cells trigger a tumor-specific immune response in the tumor’s microenvironment. The combination of viral infection, cell deterioration, new antigens, and activation of pathways that signal cell danger prevents the tumor from evading the immune system. [2][3]
In addition to being able to kill cancer cells, viruses can also be genetically altered to carry other genes directly into them, increasing the protocol’s ability to destroy the tumor cells. Recent studies have shown that though tumors often generate an anti-immune effect that protects them from the immune system, viruses can be programmed to carry genetic information that counters this effect. Combining virotherapy with immunotherapy can enhance the impact of both treatments further.[2]
Successful Cancer Treatments Using Oncolytic Virotherapy
Around the world, virotherapy has been successfully used to treat head and neck tumors and other types of cancers, but its acceptance in the United States has been more gradual. In 2014, a clinical trial conducted at the Mayo Clinic in Rochester, Minnesota, was the first to demonstrate the impact of oncolytic virotherapy on multiple myeloma. At that time, two patients received a single intravenous dose of an engineered measles virus known to be selectively toxic to myeloma plasma cells. One of the patients experienced complete remission of her cancer, while the second one did not respond as well, but her imaging studies showed that the virus had specifically targeted the sites of tumor growth. Both patients were given the highest possible dose, had limited previous exposure to measles (and therefore fewer antibodies to the virus), and had no remaining treatment options.[4]
In 2015, the FDA approved the first oncolytic virus for the treatment of cancer: T-VEC was approved for use in melanoma patients with injectable but non-resectable lesions in the skin and lymph nodes. It works by isolating human herpes simplex virus 1 with copies of two neurovirulence factors deleted. This gave it the capacity to establish an infection in the malignant cells but not in normal cells. The virus was also modified with the addition of a colony-stimulating factor that recruited and activated antigen-presenting cells, giving T-VEC the ability to promote a tumor-targeting immune response. Importantly, T-VEC retained susceptibility to anti-HSV-1 medications, ensuring patients’ protection against the virus.[5]
Clinical trials of oncolytic virotherapy are continuing, with many tests being conducted for its use in treating triple-negative breast cancer, glioblastoma, and other cancers.[6]
How Are Oncolytic Viruses Administered?
Though oncolytic viruses largely remain in the clinical trial stage, researchers have identified a variety of ways that the therapy can be administered based on what type of cancer is being treated. In solid tumors, the viruses are generally injected directly into the tumor. This method, known as intratumoral delivery, is usually used on tumors that are near the skin’s surface. It keeps the virus from affecting healthy tissues or being attacked by the immune system before it has the chance to take effect against the tumor.
Viruses can also be injected into the abdomen, into the spinal fluid, into the bloodstream, or just under the skin. Each approach is dosed differently and on different schedules.[7]
Combining Oncolytic Virotherapy with Other Therapies
As is true of many innovative cancer treatments, researchers are exploring both the efficacy of the new treatment on its own and how it may impact the effectiveness of both traditional and newly introduced treatments.
Oncolytic Viruses and Chemotherapy
Studies have shown that combining oncolytic viruses with chemotherapy can increase the effectiveness of treatment, as well as prevent chemotherapy drug resistance. An investigation using a tumor suppressor p53-expressing oncolytic adenovirus against osteosarcoma cells showed effectiveness at killing the cancer cells and the suppression of tumor growth despite the tumor model being consistently resistant to the doxorubicin chemotherapy that was used.
Oncolytic Viruses and CAR-T Cell Therapy
A two-pronged approach is being tested at the Mayo Clinic by Dr. Richard Vile, Ph.D., who is leading research that combines oncolytic virotherapy with CAR-T cell therapy to target solid tumors from liver cancer. CAR-T cell therapy is a regenerative immunotherapy that involves genetically modifying a patient’s T-cells to recognize and stop cancer. It has proven effective in many types of cancer because the CAR-T cells are highly targeted to tumor cells and have fewer side effects than traditional cancer treatments.[8]
According to Dr. Vile, Loading the oncolytic virus onto CAR-T cells may give us three levels of killing. First, the CAR-T cells target the tumor and kill some of the cells. Next, it delivers the oncolytic virus, which infects tumor cells, replicates, and kills them. Third, that alerts the immune system of the patient to the fact that there’s something majorly wrong. The immune system starts to see the cancer and starts to react against it and kill it.”[8]
Oncolytic Viruses and Checkpoint Inhibitors
In another study investigating the combination of oncolytic viruses with the checkpoint inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda), researchers from the University of Pittsburgh School of Medicine injected a single dose of a modified oncolytic virus into mice infected with a melanoma resistant to the immunotherapy drugs. The oncolytic virus alone led to tumors disappearing in 20% of the mice, but when the mice received the Opdivo and Keytruda after the oncolytic virus, tumors disappeared in two-thirds of the animals. Mice that received only the checkpoint inhibitors or an unmodified version of the virus died from their disease within a month.[2]
Is There an Oncolytic Virotherapy Treatment for Mesothelioma?
Malignant mesothelioma is an extremely challenging and aggressive form of cancer that has proven resistant to both traditional and innovative treatments. Multimodality treatments employing a combination of surgery, radiation, and/or chemotherapy provide just a year or two of survival, and that depends upon the individual patient’s condition, the stage of their disease, and their histology. Because mesothelioma tumors are localized and provide direct intra-tumoral access for injection, and because presently available therapies have shown such limited improvement, they represent a potential candidate for oncolytic virotherapy, and multiple studies are in process.[9]
Numerous early-phase clinical studies are being conducted to investigate the use of oncolytic virotherapy for malignant pleural mesothelioma. These are investigating the use of adenovirus, herpes simplex virus type 1, measles, and Newcastle disease virus, as well as VSV, NDV, reovirus, and Sendai virus. While most of these studies have investigated oncolytic therapy on its own, some have successfully combined oncolytic virotherapy with chemotherapy, radiation, and surgery. The results thus far have shown that the therapy is safe but has limited efficacy on its own, leading to more studies scheduled for the future of combination therapy. A study combining oncolytic virotherapy and immune checkpoint inhibitors in patients with small-cell lung cancer indicated increased efficacy, and with clinical trials demonstrating the safety of the treatment, it is now moving into human trials.[9]
Does Oncolytic Virotherapy Have the Potential to Cure Mesothelioma?
Malignant mesothelioma is a rare and aggressive form of cancer that is currently considered incurable, but oncolytic virotherapy shows great promise as a potential breakthrough. While we’re a long way from knowing whether this approach will lead to a cure, it offers hope for improved outcomes and longer survival times for patients.
Oncolytic virotherapy is being tested in clinical trials that provide patients the opportunity for early access to its benefits while advancing medical research. This emerging therapy holds significant potential for transforming cancer care.
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