Oncolytic Viruses – Enemy of My Enemy Is My Friend

Two prongs are better than one


by Ryan Mateja, PhD

Our immune system has the ability to detect pathogens by recognizing differences in protein structure at the atomic level.1 When tumors arise they can be detected by the immune system as pathogens and then subsequently targeted for destruction. To circumvent destruction, however, tumors have developed ways to stay alive, such as limiting their display of mutated antigens to avoid detection or dampening immune responses by disabling immune effector cells.2 The advantage cancer cells possess enabling them to survive in a healthy immune system comes at the expense of having other deleterious abnormalities.


One significant abnormality involves a limited ability of cancer cells to respond to infection by a virus. A new class of anticancer drugs called oncolytic viruses attempt to take advantage of this viral susceptibility by engineering viruses to infect tumor cells that are unable to infect normal tissue. Once infected, the therapeutic agents lead a two-pronged attack by selectively replicating inside the cancerous cells at the main tumor site causing them to burst, while simultaneously inducing a systemic immune response to kill malignant cells that have traveled away from the main tumor.3


The idea of using viruses to selectively attack cancer cells is not a new one. In fact, the first attempts at intentionally using a virus to infect and treat cancer began in the mid-20th century. At that time, research was focused on naturally occurring oncolytic viruses since the ability to engineer a custom virus to treat cancer was a far off dream. Currently, with the ability to engineer viruses we have numerous oncolytic viruses in clinical development, with the majority being in early-phase clinical trials. Two of the most prominent viruses currently in phase-III trials for cancer therapy are adenoviruses and herpesviruses.4

Adenoviruses wreak havoc on tumor cells, ripping them apart by using the host cellular mechanisms to replicate. Viruses can be engineered not only to directly destroy cancer cells, but also to trigger long lasting immune system response that will prevent the tumor from spreading in the future.

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Adenoviruses

Adenoviruses are very common viruses which can be transmitted through aerosols and direct contact. They cause a wide range of illnesses, including the common cold. Being relatively easy to modify and able to accommodate large transgenes, they are good candidates to engineer to selectively target tumor cells and also act as vehicles to administer targeted therapy.5 One engineered adenovirus being studied is CG0070, developed by Cold Genesys, Inc.

While the exact mechanism of how all oncolytic viruses mediate antitumor activity is incompletely understood, their effectiveness is thought to be rooted in their ability to elicit two distinct mechanisms of actions similar to the two-pronged approach of CG0070.

infectious disease

The first mechanism of action is local and involves the virus being engineered to carry promoters that allow it to selectively target cancer cells. Once the virus targets and infects the tumor cells, it replicates and subsequently kills the host tumor cell. CG0070 has also been engineered to carry the gene for granulocyte macrophage colony-stimulating factor (GM-CSF), which is a naturally occurring protein secreted by the body’s immune system. GM-CSF plays a role in the second mechanism of attack, which occurs when it’s released by the lysed cancer cells along with more CG0070 to infect other cancer cells. The lysed cancer cell also releases tumor-specific antigens along with other immune stimulating proteins which initiate an immune response at the tumor site. The GM-CSF attracts dendritic cells which process the tumor-specific antigens and present them to cytotoxic (killer) T-cells. The cytotoxic T-cells then travel throughout the body recognizing and attacking cancer cells that have moved away from the main tumor site. Currently, CG0070 is going through phase III clinical trials for the treatment of bladder cancer.6

Herpes simplex virus


Herpes simplex viruses (HSV) are in the same family as the chickenpox virus (varicella) and were one of the first viruses to be studied as an oncolytic virus for cancer therapy. In addition to being well understood, it is relatively harmless and is more likely to pose fewer risks since in its natural state it only leads to cold sores. Talimogene laherparepvec (T-Vec) is one of the most notable oncolytic viruses and is HSV type 1 (HSV-1) based. Since HSV-1 can infect many types of cells, T-Vec contains two deletions to reduce pathogenesis and increase cancer cell infectivity.4 The first deletion improves cancer cell targeting by preventing the infection of neurons and other non-dividing cells while still allowing infection and lysis in cancer cells. The second deletion results in increased presentation of viral antigens allowing immune-mediated destruction of cancer cells that propagate oncolytic HSV-1. Like CG0070, the gene encoding GM-CSF has been engineered into T-Vec to improve the second pronged-attack of systemic anti-tumor immunity. Whether or not this second systemic immune response is actually happening in patients who have received T-Vec has not been proven as of 2016.7 Currently T-Vec is the first approved oncolytic virus in the West (October 2015) and provisionally approved in Europe (December 2015).7,8

Weapons of Oncolytic Virus Warfare


The effectiveness of oncolytic viruses appears to be the result of their two-pronged approach of direct tumor lysis and subsequent trigger of systemic immune responses. The systemic immune response suggests oncolytic viruses might provide long-term results due to the possibility that they can eliminate cancer cells from all sites of metastases. While being an integral part of this process, the immune response is also a double edged sword and presents some intrinsic problems. For instance, if the immune response is too strong it may block viral replication and ongoing infection of tumor cells. Similarly, immunocompromised patients may not be good candidates for this therapy because they might not have a strong enough immune response to stimulate anti-tumor activity at sites away from the initial tumor after viral infection. Nevertheless, with the promises of current products undergoing development and the recent success of T-Vec, it appears that in the future the two-pronged approach of oncolytic viruses will play a large role in the fight against cancer.


References

  1. Glenney JR Jr, Zokas L, Kamps MP. Monoclonal antibodies to phosphotyrosine. J Immunol Methods. 1988 May 9;109(2):277-85.
  2. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64.
  3. Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat Biotechnol. 2012 Jul 10;30(7):658-70.
  4. Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015 Sep;14(9):642-62.
  5. Oncolytic virus. (2017, March 09). In Wikipedia, The Free Encyclopedia. Retrieved March 09, 2017, from https://en.wikipedia.org/w/index.php?title=Oncolytic_virus&oldid=769544197
  6. https://clinicaltrials.gov/ct2/show/NCT02365818
  7. “FDA approves Amgen’s Injected Immunotherapy for Melanoma”. Reuters. 27 October 2015.
  8. Bilsland AE, Spiliopoulou P, Evans TR. Virotherapy: cancer gene therapy at last? F1000Res. 2016 Aug 30;5. pii: F1000 Faculty Rev-2105.