One therapeutic approach to harness the immune system in the fight against cancer revolves around the use of viruses, sometimes also referred to as virotherapy. As microscopic invaders, viruses infect and reproduce inside cells. This can kill healthy cells and cause disease. Some viruses, however, preferentially target and infect cancer cells. These oncolytic viruses can be used as immunotherapy against cancer, and there are two main ways that explain how oncolytic viruses are thought to work.
Injected directly into cancerous lesions, they first replicate inside the cancer cells where they cause cell death and lysis. As the infected cells are destroyed, they release new virus particles into the blood stream to infect and destroy other cancer cells. The ruptured cancer cells secondarily stimulate antitumor immune responses in the host by releasing tell-tale markers or tumor antigens into the tumor microenvironment. These antigens are taken up by antigen-presenting cells, which then stimulate T cells to attack and obliterate cancer cells elsewhere in the body.
The strategy to use viruses to treat cancer builds on a phenomenon that has been appreciated for more than a century. Physicians in the 1800s noted that their cancer patients sometimes unexpectedly went into remission after experiencing a viral infection. These case reports later inspired doctors, particularly in the 1950s and 1960s, to gain a better understanding of those therapeutic effects. Malignancy can suppress normal antiviral responses, and sometimes the mutations that spur tumor growth also make cells more susceptible to infection. Viral infection can thus destroy tumor cells while leaving neighboring healthy cells untouched.
Some of today’s investigational oncolytic viruses are meticulously engineered to alter their virulence and to reduce their ability to cause disease by harming healthy cells. In addition, some oncolytic viruses have been genetically modified through the insertion of a gene that encodes signaling proteins to amplify the antitumor immune response.
Talimogene laherparepvec (T-VEC), a herpes virus-based immunotherapy developed by BioVex, Inc. under the name OncoVEXGM-CSF and acquired by Amgen in 2011, significantly increases the durable response rate in patients with metastatic melanoma. Approved by the FDA in October 2015 under the brand name Imlygic®, it is the first commercially available oncolytic virus therapy of its kind in the United States.
The treatment that is injected into the cancerous lesions is thought to work by directly killing melanoma cells and by stimulating an immune response against the tumor. An oncolytic virus that is based on herpes simplex virus type 1, T-VEC has also been modified to include a gene that codes for granulocyte-macrophage colony-stimulating factor (GM-CSF), a protein that stimulates the production of immune cells in the body.
In a Phase III clinical trial, more patients assigned to T-VEC achieved a durable response—a decrease in size of their skin and lymph node lesions—compared with patients assigned standard of care. Although the virus both shrank tumors in people with advanced melanoma and extended patient survival by a median of 4.4 months, the survival benefits just failed statistical significance. The FDA consequently noted that T-VEC was not associated with an improvement in overall survival.
The approval of Imlygic among other recent developments in cancer immunotherapy have rejuvenated the interest in virotherapy as a platform for the development of antitumor immunotherapy regimens. Several reviews have detailed exciting new approaches in this area, as well as emphasized the potential success of such agents. They will most likely achieve their greatest potential as part of combination therapeutic anticancer strategies.
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