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Can viruses be heroes? It is well-known that some viruses can cause severe infections in the body. However, when modified in the correct way, these small molecular entities can be used as an additional arsenal in the immune tool bag, to kill even bigger and scarier enemies… such as cancer. Here, we review the recent advances made in the field of immunotherapy that uses viruses to systematically target and destroy cancer.
Despite ground-breaking advances made in the field of cancer therapy and treatments, there still remains a distressingly high rate of cancer-related mortality. The main goal of anti-cancer therapies is to slow the growth of cancer, while keeping the healthy and combative cells alive and functional. In my previous articles, I have outlined conventional approaches of using chemotherapy as well as precision anti-cancer strategies by using chimeric antigen receptor (CAR-T) and Bi-specific T cell engagers (BiTes) that have shown positive results in the clinic. Here, I will discuss another innovative approach by employing select viruses to infect cancer cells to eventually kill them. This strategy of using cancer-specific virus therapy, is referred to as oncolytic virotherapy and those viruses are called oncolytic viruses (OV).
By the 1950’s, the cancer field had already established that conventional approaches of combining surgery and chemotherapy were not always able to cause remission in all cancers. Following this cumbersome finding, physicians and scientists joined forces to make earnest efforts to find alternative approaches to treat cancers as individual diseases rather than “one trick for all” in order to make sense of the complex biology of cancer metastases. Based on the observation that cancer growth was debilitated during viral infections, scientists experimented with injecting viruses into cancer cells, but were discouraged due to high overall toxicity. These findings were primers to the conviction that not all viruses can be used to treat cancers, and those that could be used should not contribute towards toxicity.
Viruses, as any other parasite, need to infect and multiply inside of a host in order to complete their life cycle. Oncolytic viruses are a specific type of viruses that can kill cancer cells, leaving the healthy cells in the body – unharmed. Based on to-date scientific findings, OVs detect and kill cancer cells in four ways: 1) OVs can detect cancer cells with impaired signaling, in that they are under checked and growing faster than expected; 2) OVs can be engineered so that they have deliberate mutations or foreign genes inserted in them to detect cancer cells better; 3) they produce toxic proteins that can kill cancer cells and 4) they start a chain of reactions that cause cancer cell death. Figure-1 summarizes these mechanisms broadly in to how OVs can boost the immune responses by either killing large clusters of cancers immediately or by creating and immune environment where they recruit killer cells to make for an efficient cancer cell lysis.
But, what happens if the person has already been infected with the virus years before the treatment? Let’s say you had a viral infection before and your body made antibodies to keep the immune system alert in case you get exposed to the same virus again. This means that there’s an existing pool of anti-virus antibodies in the bloodstream from a previous virus infection that will prevent the oncolytic virus to do its job and infect cancer cells. Taken together, these are the reasons why which OV is used for treating a specific cancer is very critical and hugely depends on patient’s immune history.
To date, the American Food and Drug Administration has only approved one oncolytic virus to treat metastatic melanoma. This oncolytic virus called Talimogene Laherparepvec, or T-vec is commercially sold by Amgen and has been successfully used to treat advanced melanoma type cancers. T-vec is made from a genetically modified herpes virus – a close relative of the virus that causes cold sores, and when injected into skin cancer lesions, is able to enhance the immune response to kill and fight cancers that can not be easily operated. According to the Melanoma Research Alliance, while the exact details of mechanism by which T-vec works are not known, it is believed that T-vec upon injection into cancer cells can generate pieces shedding off the tumor cells and stimulate the immune system by releasing proteins (called GM-CSF) that are important for activation of our body soldiers the killer T cells.
Taken together, the elegant nature of viruses and careful engineering to infect and debilitate cancer growth are starting materials for a precision approach towards blocking advanced stage cancers that can not be easily removed or respond to conventional approaches of chemotherapy and radiation. Recently, T-vec has been administered to patients in combination with the checkpoint inhibitor therapies that have been discussed in previous articles. Although, a small study, the results showed 90% response to the combination therapy suggesting OV can be combined with other cancer treatments to enhance the immune system by enriching the arsenal of anti-tumor responses.
- Sun et al. Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series. J. Immunotherp Cancer. 2018.
- Russel and Peng. The emerging role of oncolytic virus therapy against cancer. Chin. Clin. Oncol. 2018.
- Lawler SE et al. Oncolytic viruses in cancer: Review. JAMA Oncol. 2017; 3(6): 841-849.
- Header image: Gopinath K, Gene Online. June 28, 2018.
- Figure-1 generated using Biorender