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VIRUSES BLASTING CANCER

Last week, Johnson & Johnson (New Brunswick, NJ ) announced that their biotech arm Janssen Labs (Rariton, NJ) is investing up to $1 billion dollars to acquire BeneVir, a small biotech based in Rockville, Maryland, which focuses on oncolytic virus development. Earlier this year, Merck (Kenilworth, NJ) acquired Australian oncolytic virus company Viralytics (Sydney). Once considered a long shot, this type of immunotherapy is now being taken seriously by bluechip biopharma players. In this WEEKLY, we’ll review the fundamentals of how oncolytic viruses work and take a look at the increasingly crowded pipeline.

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 an immune response to fight cancer is no easy task.  Oncolytic viruses are created in the lab by genetically modifying existing viruses in at least two ways:

  1. Making the virus safe by removing genes that cause sickness in people
  2. Engineering the virus to recognize and kill cancerous cells and disregard healthy, non-cancerous cells

The oncolytic virus follows the same life cycle as any virus—once inside the human body it hunts down and enters its host cell. In this case, the host happens to be cancer cells. As the oncolytic virus multiplies inside of the tumor, it causes these cells to burst open, killing them. Spewing from the burst are new virus particles that target remaining tumor cells. The virus also activates the immune system, bringing in a second line of attack..

Most oncolytic viruses are being tested as both stand-alone treatments and in-combination with other immunotherapies such as checkpoint inhibitors.

INSIDE IMLYGIC

Amgen’s (Thousand Oaks, CA) Imlygic, which targets melanoma, is currently the only FDA approved oncolytic virus. 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, enabling Imlygic to replicate only in cancer cells (not in healthy human cells.)
  • Deletion of viral gene ICP47, helping the virus evade immune detection.
  • Increased activation of the viral gene US11, resulting in more viral replication in tumor cells so a larger number of cancerous cells are killed.
  • Insertion of a gene for the human protein GM-CSF, which “revs up” the immune system, aiding in the overall immune response against the tumor.

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.

STEALTHY INVADERS

BeneVir’s oncolytic virus caught Janssen Lab’s attention because it incorporates the company’s “T-stealth” technology, an oncolytic virus platform also built on a herpes simplex 1 virus that selectively infects and kills tumor cells. The T-stealth platform incorporates an additional viral gene that prevents T-cells from recognizing and attacking the therapeutic virus itself.  This innovation should allow the virus to spread to more cells within a tumor. The T-stealth oncolytic viruses are in preclinical development for the treatment of solid tumors.

ONCORUS ON THE OFFENSE

Another modified herpes virus, ONCR-001, is being developed by Oncorus (Cambridge, MA)  for the notoriously difficult-to-treat brain cancer, glioblastoma. Like Imlygic, ONCR-001 has been modified to selectively target tumor cells. Instead of blocking viral replication, Oncorus scientists engineered a “suicide switch” into their virus that is activated only in healthy cells. When ONCR-001 infects healthy cells, the switch is triggered, and the virus is destroyed. The switch is not triggered by tumor cells, leaving the virus fully able to kill the enemy.

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 already used as a vaccine for smallpox, meaning that it already has a decades-long safety record, 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. GL-ONC1 is in Phase II clinical testing for a variety of solid tumors.

The company is also developing oncolytic viruses with genes for “therapeutic payloads” — proteins and therapeutic antibodies  that will boost the patient’s immune response to the cancer because these payloads will be produced inside the cancer cells. 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.

ONCOLYTIC PIPELINE
COCKTAIL FODDER: RENEGADE VIRUSES OF THE PAST

The idea of using viruses to challenge cancer is cutting-edge, 21st-century science, but the inkling of a cancer-fighting virus was first observed more than a century ago. In 1904, an editorial published in the American Journal of Medical Science revealed a spontaneous regression of cervical cancer occurred after administration of a rabies vaccination. A few years later, a similar phenomenon occurred: the remission of lymphoma after a measles virus infection. Our modern understanding of viruses at the molecular level combined with our increased ability to manipulate genes made this century-old idea a medical reality of today.

emily burke
Emily Burke, PhD

Author

Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and ISIS Pharmaceuticals. As a PhD molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings worldwide. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.

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