The FDA approves the use of an oncolytic virus as melanoma therapy

The FDA recently approved an engineered herpesvirus called talimogene laherparepvec (T-VEC) as a treatment for advanced melanoma1. This is the first of the oncolytic viruses to be approved for use in the United States as a cancer treatment2. This is exciting news because there are dozens of oncolytic viruses currently in clinical trials for different kinds of cancers, and the approval of T-VEC will hopefully pave the way for further research and development for this class of therapies.

Operating Room, Canadian General Hospital, Orpington, England
Helen Kendall, Anesthetist, at the head of the table.
The idea to use viruses to kill cancer cells has been around for a long time. As early as the 1800s, physicians noticed that some cancer patients seemed to go into remission after a viral infection. Case reports of regression in patients with cervical cancer, Burkitt lymphoma, and Hodgkin lymphoma were noted. This led some physicians in the 1950s and 1960s to experimentally injecting cancer patients with different viruses including vesicular stomatitis virus (VSV), poliovirus, adenovirus, Coxsackie virus, and others, hoping that they would kill tumors – unfortunately for the patients, sometimes the injections killed them along with the tumors. In those cases that did not result in death to the patient, there were other complications such as flu-like symptoms and uncontrolled infection. In other cases, the immune response destroyed the virus before it had a chance to destroy the cancer3.
Oncolytic viruses kill cancer cells by lysing them (hence the term oncolytic)4, releasing new viral particles to infect neighboring cells, thereby activating the host immune response and killing the tumor. There are wild-type viruses, or viruses that occur naturally, that can act as oncolytic viruses. These include the previously mentioned VSV and poliovirus, as well as reovirus. The viruses that are in clinical trials now are engineered by various methods. They can target specific tumor types by engineering the viral coat proteins to target only tumor cells, leaving non-tumor cells uninfected. Viruses can also be engineered by deleting viral genes to eliminate those functions of the virus that are not necessary in tumor cells. An example of this is the thymidine kinase enzyme, which is responsible for DNA synthesis and is only expressed in actively dividing cells. Viruses such as herpesvirus and vaccinia virus require the presence of thymidine kinase in order to replicate in non-dividing cells, so if that gene is deleted then the virus will only be able to reproduce in cells that are actively replicating, such as cancer cells5.
T-VEC is a herpesvirus that is engineered to stimulate the immune system and has a significantly reduced ability to cause herpes in people1, 2. T-VEC acts by releasing the protein GM-CSF and other antigens that signal to the immune system that the cancerous cells need to be eliminated throughout the body. GM-CSF attracts dendritic cells, and they go on to present tumor cell antigens to T cells, which destroy other cancer cells1, 2.

Image from: Wikipedia
T-VEC currently has to be injected directly into tumors, but it is able to destroy cancer cells throughout the body as well. In results published this year, the virus shrank tumors in patients with advanced melanoma, and increased survival by a median of 4.4 months. There were no fatal treatment-related adverse events, and the most common ones were flu-like symptoms1, 2.

Scientists are interested in combination therapies of T-VEC with immunotherapy, as well as being able to administer T-VEC systemically instead of injecting it directly into the tumor site6. This would help reach tumors that are present in organs that are difficult to reach via injection. However, this technique would require some way of preventing an immune response to the virus before it has a chance to reach the cancer cells, as was seen in the early trials of the mid-20th century. Do you have any ideas for ways to circumvent the immune response? Email us at tech@biolegend.com with suggestions or comments.
Contributed by Rea Dabelic, PhD.
References:
  1. Cancer-fighting viruses win approval
  2. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma
  3. Oncolytic viruses
  4. Viral oncolysis by herpes simplex virus and other viruses
  5. Viral thymidine kinases and their relatives
  6. Intelligent design: combination therapy with oncolytic viruses
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