From the American Association for Respiratory Care (AARC) 2023 annual meeting, a significant development in cancer immunotherapy is the breakthrough involving personalized mRNA vaccines that target patient-specific neoantigens. In a phase 2 trial, combining such a vaccine with PD-1 checkpoint immunotherapy for patients who had undergone surgical resection for high-risk melanoma led to a reduction in the risk of recurrence or death by 44%. This approach is distinct from traditional cancer vaccines which target tumor-associated antigens that might also be present in healthy tissues. In this article, we’ll review the fundamentals of how oncolytic viruses work and take a look at the increasingly crowded pipeline.

Oncolytic viruses are a form of immunotherapy—a 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 the tumor, it causes these cells to burst open, killing them. New virus particles that target the remaining tumor cells are spewing from the burst. The virus also activates the immune system, bringing in the second line of attack.

Most oncolytic viruses are tested as standalone treatments and combined with other immunotherapies such as checkpoint inhibitors.

Amgen’s (Thousand Oaks, CA) Imlygic targets melanoma and 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 and activation of a host immune response targeting the virus-infected tumor cells.

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 to treat solid tumors.

Another modified herpes virus, ONCR-001, is being developed in Phase 1 trials by Oncorus (Cambridge, MA) for the notoriously difficult-to-treat brain cancer, glioblastoma. Like Imlygic, ONCR-001 has been modified to target tumor cells selectively. Instead of blocking viral replication, Oncorus scientists engineered a “suicide switch” into their virus 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.

San Diego-based Genelux is adapting the vaccinia virus as an oncolytic virus to treat a variety of solid tumors. Vaccinia is already used as a vaccine for smallpox, meaning 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 cancer because these payloads will be produced inside the cancer cells. This approach is a clever response to the fact that most therapeutic antibodies cannot completely penetrate solid tumors due to their relatively large size. Using an oncolytic virus to penetrate the tumor and deliver genes instructing the tumor itself to make the antibody could be a game-changing workaround.

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 the administration of rabies vaccination. A few years later, a similar phenomenon occurred: lymphoma remission 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.