What is the mechanism of action of oncolytic viruses treating cancer?

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Mudassir Ali 8 months 1 Answer 126 views

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  1. Here is a nice infographic concerning the MOA (mechanism of action) of oncolytic virotherapy. The original version can be obtained from here[1] , and it also appeared in Scientific American (I still can’t understand why the hell Nature put a paywall on an article written for public education purpose). Here I make an elaboration on several MOA.

    Direct host cell destruction via viral infections

    The most straightforward is using viral replication itself to destroy the cancer cells. Oncolytic viruses are engineered human viruses, or unmodified animal viruses, which selectively infect cancer cells, while leaving healthy cells alone. By infecting the cancer cells, oncolytic viruses burst the host cells, releasing thousands of copies of themselves, which go on to infect more cancer cells. Some viruses including picornaviruses, VSV and vaccinia virus have a short life cycle and a large burst size (virus yield of each infected cell), which are ideally suitable for this purpose.

    Besides direct destruction of infected cells, some viruses such as measles virus can trigger the fusion of infected cells with adjacent cells, forming giant, multinucleated syncytia. Once the syncytia are formed, cancer cells lost their ability of dividing and die within a few days. Such strategy enables simultaneous destruction of multiple cells in a single infection event, a phenomenon termed “bystander effect”.

    Expressing therapeutic transgenes

    To further augment the tumor killing efficiency of these viruses, many viruses are engineered to express therapeutic transgenes. Some viruses are engineered to express a “suicide gene”, which forces the cancer cells to self destruct. For example, Toca 511 is a retrovirus armed with a yeast cytosine deaminase (CD), which converts 5-FC, a nontoxic prodrug, into 5-FU, a potent chemo drug. The chemo not only kills the infected cancer cells, but also adjacent uninfected cancer cells via bystander effect. It also removes MDSC as well as other immune inhibitory cells, thereby potentiating an anti-tumor immune response. Another example is MV-NIS, which is an engineered measles virus for myeloma treatment. The virus incorporates a thyroid protein NIS, which forces the infected cells to absorb radioactive iodines. Because myeloma is highly radiosensitive, such strategy markedly enhanced the therapeutic efficacy, and enables a real-time monitoring of in-vivo viral replication and spread via PET-CT.

    Because immunotherapy became so hot in recent years, many oncolytic viruses also incorporate various immune modulatory genes, such as cytokines (GM-CSF, IL-12 etc), chemokines and antibodies (CTLA-4, PD-1 or BiTE). The first approved oncolytic virus T-vec is an engineered herpes simplex virus expressing GM-CSF, which attracts monocytes into the tumor bed and prompts their maturation into antigen presenting cells. One advantage of using viruses as delivery vectors is that the transgene expression is restricted to the tumor bed, thereby avoiding systemic toxicity (for example, IL-12 is a potent immune stimulatory cytokine, but is too toxic to be given systemically).

    Although arming the viruses with transgenes is an attractive strategy, it should be noted that NOT all viruses are suitable for this strategy. Most viruses lack the capacity or genomic flexibility to accommodate a foreign transgene. Only a few viruses including adenovirus, vaccinia virus, herpes simplex virus and mononegavirales (e.g., measles, VSV) are successfully engineered to express transgenes.

    Destroying tumor vasculature

    Cancers require blood irrigation to thrive; as a result, they often stimulate excessive blood vessel formation, a phenomenon termed “tumor angiogenesis”. Surprisingly, a few oncolytic viruses like VSV and vaccinia virus can infect the endothelial cells of the tumor blood vessels, while vascular endothelial cells are healthy cells, which are not supposed to be infected. Further studies revealed that cancer cells stimulate the vessel growth by producing excessive amount of VEGF, which activates the VEGFR pathway in vascular endothelial cells. The activated VEGFR pathway on one hand drives the proliferation of these cells, OTOH it turns off the antiviral interferon pathway, therefore sensitizing them to infections of certain viruses. So these viruses function like antiangiogenic therapy. However, unlike conventional angiogenesis inhibitors, which just stall the tumor vessel growth, viral infection directly destroys these vessels, which triggers massive blood clotting and ischemic tumor necrosis.

    Such attribute of infecting tumor blood vessel walls is particularly desirable for intravenous administration (in contrast to most oncolytic viruses, which are given via intratumoral injections). It’s counterintuitive that tumor blood vessels are less efficient at drug delivery despite being more “leaky”. As a result, oncolytic viruses given intravenously suffer from poor bioavailability. OTOH, direct infection of tumor blood vessels skipped the inefficient extravasation step, thereby dramatically enhancing the bioavailability. There are several ongoing clinical trials evaluating the efficacy of an oncolytic vaccinia virus JX-594 in renal cell carcinoma and hepatocellular carcinoma[2] ; both are known tumors rich in vasculature.

    Immune activation

    Given that immunotherapy has become a hot topic nowadays, its not surprising that most (if not all) virotherapy teams highlight the potential of oncolytic viruses as an immunotherapy. Indeed, viruses are very effective at triggering the immune activation as their replication releases a lot of PAMP and DAMP and promotes “immunogenic cell death” (ICD) of infected cancer cells. Moreover, many viruses are armed with immune modulatory transgenes to further augment their immunogenicity. One of the most promising aspect of oncolytic viruses is that their infection can subvert the otherwise immune suppressive tumor microenvironment (TME), turning these “cold tumors” into inflamed “hot tumors”[3] , making them conducive to other immunotherapy such as checkpoint inhibitors and CAR-T cells.

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