Engineering Viruses To Attack
Getting bacteria-eating viruses to combat antibiotic resistance isn’t the only way viruses are being hacked to defend team homo sapien. This week, we’ll turn our attention to another benevolent use of viruses: cancer-fighters known as oncolytic viruses.
Oncolytic Virus Primer
Oncolytic viruses are an immunotherapy — a type of therapy that harnesses the power of a patient’s immune system to combat a disease. Getting a virus to trigger the immune response to fight cancer is no easy task, the process involves engineering the virus to selectively infect and kill cancer cells. Oncolytic viruses are created in the lab by genetically modifying existing viruses in at least two ways:
- Making the virus safe by removing genes that cause the virus to make people sick
- Engineering viral surface proteins so the virus recognizes and binds to the cell receptors of cancerous cells, disregarding the healthy, non-cancerous cells
The oncolytic virus follows the same life cycle as any virus—once inside the human body it hunts down, attaches to, and enters its host cell. In this case, the host happens to be cancer cells! The virally infected cancer cells are destroyed via the process of cell lysis—as the oncolytic virus multiplies inside of the cells, it causes the cancer cells to burst open which kills them. Spewing from the burst cells are new infectious viruses that further target remaining tumor cells. The presence of a replicating virus also activates the immune response, so the cancerous area is further attacked.
Additional modifications may also be made to the virus, depending on the characteristics of the targeted cancer. For example, an oncolytic virus might be modified to produce proteins that stimulate the immune system or directly attack the tumor.
Most oncolytic viruses are tested both as “stand-alone treatments” and “in-combination with other immunotherapies” — such as checkpoint inhibitor therapies — to help fully activate the immune response against cancer. Let’s take a look at the unique features of a selection of oncolytic viruses on the market and in development.
Inside Of Imlygic
Viruses can be thought of as very simple packages of genetic material — DNA or RNA — encapsulated in a protein package. Like the human genome, viral genomes code for proteins required by the virus. Some of these proteins enable the virus to make copies of itself (replicate), or to evade the human immune response. It is often necessary to modify the viral genome in order to safely use a virus as a therapeutic, but how?
Amgen’s (Thousand Oaks, CA) Imlygic is the only FDA approved oncolytic virus, aiming to attack melanoma. The virus used in Imlygic is a modified herpes simplex 1 virus. The modifications made to Imlygic to ensure safety and efficacy include:
- Deletion of viral gene ICP34.5. This gene codes for a protein that enables the virus to replicate in human cells by blocking a human protein known as PKR. PKR prevents viral replication. It is less active in most tumor cells, so this makes the virus able to selectively replicate in tumor cells.
- Deletion of viral gene ICP47. This gene codes for a viral protein that thwarts the immune response by turning off a process called antigen presentation. Normally, one of the key ways the immune system “knows” to attack a virally-infected cell is by recognizing antigens (or fragments of viral proteins) displayed on the infected cell’s surface. Turning this process off helps the virus evade the immune system. Turning it back on prompts the immune system to attack virus-infected tumor cells.
- Activating the earlier expression of the viral gene US11, resulting in increased viral replication in tumor cells.
- Insertion of a gene for the human protein GM-CSF, which activates the immune system, aiding in the overall immune response toward the tumor triggered by viral infection.
Taken together, these modifications create a virus that selectively replicates in tumor cells, resulting in their direct destruction as well as activation of a host immune response targeting the virus-infected tumor cells.
Oncorus On The Offense
Oncorus (Cambridge, MA) is also developing a modified herpes virus, ONCR-001, for the treatment of cancers, including the notoriously difficult-to-treat brain cancer, glioblastoma. Like Imlygic, ONCR-001 has been modified to selectively target tumor cells. Unlike Imlygic, ONCR-001 retains all viral genes needed for viral replication.
So, how is safety maintained in the presence of an oncolytic virus that is actively replicating? Oncorus scientists have figured out a clever way to take advantage of a key difference: the types of microRNAs produced by healthy cells vs. cancer cells.
MicroRNAs are a type of “regulatory RNA” that promotes the degradation of a target messenger RNA (mRNA — the RNA that gets turned into proteins). This means that different target sequences will be recognized in healthy cells vs. cancer cells. By engineering sequences that microRNAs from healthy cells will recognize, Oncorus scientists can ensure the viral mRNA will be destroyed in any healthy cells it infects. No viral mRNA, no viral proteins, no virus. Because these microRNAs are not present in tumor cells, ONCR-001 is able to produce viral proteins and new viral particles freely when it infects those target cells. ONCR-001 has shown strong ability in fighting glioblastoma in preclinical models.
The Genesis Of Genelux
San Diego-based Genelux is adapting the vaccinia virus as an oncolytic virus for the treatment of a variety of solid tumors. Vaccinia is the scientific name for the cowpox virus — the virus that is used as a vaccine for smallpox. Because of its decades-long use as a vaccine, researchers have confidence the virus is safe to use in humans, although the modified version must still undergo safety testing.
Their lead product, GL-ONC1, selectively replicates in tumor cells and tumor-associated blood vessels, directly killing tumors while cutting off their blood supply. The company is also developing oncolytic viruses with genes for “therapeutic payloads” — proteins that will boost the patient’s immune response to the cancer, or even therapeutic antibodies that will then be produced inside of the cancer cell. This approach is a clever response to the fact that due to their relatively large size, most therapeutic antibodies are not able to completely penetrate solid tumors. Using an oncolytic virus to penetrate the tumor and deliver genes instructing the tumor itself to make the antibody could be a game-changing work around.
Finally, Genelux is also creating engineered virions that incorporate “imaging” proteins. For example, GL-ONC1 delivers a gene for a fluorescent protein directly to tumor cells. As the virus replicates inside of the tumor, the fluorescent signal increases. In preclinical animal testing, this has allowed non-invasive detection and imaging of tumor progression and regression in real time, and may one day be a powerful guide to physicians monitoring cancer patients. GL-ONC1 has successfully completed Phase I and is preparing to enter Phase II for a variety of solid tumors including peritoneal carcinomatosis.
With the approval of Imlygic in 2015, biotech companies, investors, and regulatory officials have recognized the strong potential of oncolytic viruses to treat cancer. The race is on to get the next oncolytic virus through the clinic: