Oncolytic Virus Therapy
The skin covering our bodies is our first line of immune defense, acting as a natural barrier. When everything works normally, the immune system is active within our skin and is our second line of defense. The immune system protects us from infection and disease, but sometimes it is prevented from doing its job.
Skin cancers can develop when tumor cells shut off the immune system’s response or when someone has an immune system that has been weakened by disease or medication. If the immune system is off, it does not kill cancerous cells and tumor development can continue. Immunotherapy (meaning “immune” + “therapy”) drugs turn the immune system’s response back on.
The immune system usually is present and vigilant within our skin. The constant vigilance helps explain why skin cancers are often responsive to immunotherapy drugs. Re-energizing immune system activity can result in an immune cell’s ability to fight cancer and kill tumor cells.
Immunotherapies like cemiplimab (Libtayo) and pembrolizumab (Keytruda) have revolutionized the treatment of many cancers, including skin cancer. Cancer cells evade our immune system attack by displaying certain molecules on their surface that make them invisible to the immune system. Immunotherapy removes these molecules and allows our immune system to identify and attack cancer cells.
Drugs like cemiplimab nivolumab and pembrolizumab belong to a specific group of immunotherapies called immune checkpoint inhibitors to describe their specific action. Immune checkpoint inhibitors work well for many patients with skin cancer, but not everyone will experience a dramatic improvement. Here we will explain a different type of immunotherapy called oncolytic virus therapy or oncolytic virotherapy. Though oncolytic virotherapy differs from immune checkpoint inhibitors, these drugs are categorized broadly as immunotherapies.
What is Oncolytic Virus Therapy or Oncolytic Virotherapy?
Oncolytic virotherapy is a treatment that uses a human virus modified in a laboratory to target and infect cancer cells while leaving most normal cells alone. After infection, the virus multiplies itself within the cancer cell. Eventually, the cancer cell will die and burst open. This outcome releases viruses around the area to infect neighboring tumor cells.
The virus is also modified with components to stimulate an immune response. When the infected cancer cell opens and releases its contents, immune cells are alerted and promote activation of the immune system. Essentially, this re-energizes the body to attack cancer using its immune system. However, in nonmelanoma skin cancers, there are no approved viruses for use in virotherapy.
Are there any Oncolytic Virotherapies in Clinical Trials?
Yes, oncolytic virotherapies are in clinical trials for many types of cancers, including nonmelanoma skin cancer. The oncolytic virotherapies may be tested alone, but often they are combined with immune checkpoint inhibitors. The combination appears to make the virotherapy work better.
For example, a recent clinical trial of oncolytic virotherapy called vusolimogene oderparepvec (RP1) was tested in combination with cemiplimab (Libtayo®), which is an approved immunotherapy drug. The clinical trial included patients diagnosed with locally advanced or metastatic cutaneous squamous cell carcinoma, sometimes referred to as squamous cell skin cancer.
In this trial, 120 patients with squamous cell skin cancer received an intralesional injection of vusolimogene oderparepvec (RP1) and cemiplimab (Libtayo®). Among the patients who received the drug combination, 48.1% had a complete response. Of the patients receiving only cemiplimab (Libtayo®), 22.6% had a complete response. Although there was better response in patients who received the oncolytic virotherapy in this trial, further follow-up is required for this therapy, and it is not currently approved by the FDA.
Many types of viruses are being tested for vaccines or oncolytic virotherapy in ongoing clinical trials. Vusolimogene oderparepvec (RP1) is made from the herpes virus. Besides the herpes virus, adenoviruses and echoviruses have succeeded developing oncolytic virotherapy and vaccines. Other types under investigation include coxsackie viruses, lentivirus, measles, poliovirus, reoviruses, vaccinia viruses, and vesicular stomatitis viruses.
How Do Ooncolytic Virotherapies Kill Cancer Cells?
The overall process provokes an immune response against cancer cells in the injected tumor. Although the mechanism is not fully understood, virotherapy uses the modified virus’s programming to copy itself repeatedly inside tumor cells. It hijacks the tumor cell’s resources, turning it into a virus-manufacturing factory. Eventually, the cell runs out of resources.
[BioRender was used to create the image.]
The dysfunction caused by the virus can lead to tumor cell death and rupture of the tumor cell (Figure 1). The contents spilled out are recognized by the immune system as alarms. Other contents released from the tumor cells are proteins that will stimulate the production of immune cells. The new immune cells will rush into the area and engage with neighboring tumor cells, killing them.
The HSV-1 virus is modified for use in the drug T-VEC. It is injected into the melanoma tumor lesion. The cancer cell begins to manufacture many viruses, using up its resources. Eventually, it will die and burst open, spilling virus out of the cell to neighboring cells. Although the cancer cell is dead, the immune system is alerted by the virus particles and becomes active. The immune activation leads to the additional killing of other cancer cells.
What Types of Cancer Can Be Treated with Oncolytic Virotherapy?
Clinical trials with oncolytic virotherapies for nonmelanoma skin cancer and Merkel cell carcinoma are ongoing. T-VEC was approved in the U.S. in 2015 for the treatment of melanoma. There are no FDA approvals for oncolytic virotherapy in nonmelanoma skin cancer. Please visit our clinical trials page for additional information about enrollment status for trials.
In countries outside of the U.S., oncolytic virotherapy is used in combination with chemotherapy and/or radiation therapy for the treatment of glioblastoma and nasopharyngeal carcinoma. In addition, phase 2 clinical trials have investigated oncolytic virotherapy against bladder, colorectal, lung, and pancreatic cancer. However, oncolytic virotherapies to treat these cancers are not approved to date.
References
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Shalhout SZ, Miller DM, Emerick KS, et al. Therapy with oncolytic viruses: progress and challenges. Nat Rev Clin Oncol. 2023;20(3):160-177. doi: 10.1038/s41571-022-00719-w.
Thomas S, Kuncheria L, Roustone V, et al. Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simple virus type 1. J Immunother Cancer. 2019;7(1):214. doi: 10.1186/s40425-019-0682-1.
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IMLYGIC® (talimogene laherparepvec) [package insert]. Thousand Oaks, California: Amgen: 2015.
Wongariyapak A, Roulstone V, Melcher AA, et al. Combination strategies incorporating oncolytic viruses and immune checkpoint inhibitors for advanced melanoma: what is the evidence? Ann Transl Med. 2023;11(10):369. doi: 10.21037/atm-2023-5.