Oncolytic virus therapy is an approach in cancer treatment that uses viruses to infect and destroy tumor cells. This method harnesses a virus’s natural ability to replicate, but directs it specifically against malignant cells. The concept has evolved from early observations of tumor regression following viral infections into a therapeutic strategy. Modern techniques allow for the modification of these viruses, enhancing their effectiveness and safety as a targeted cancer therapy.
The Mechanism of Oncolytic Viruses
The effectiveness of oncolytic viruses stems from a dual-action mechanism that both directly destroys cancer cells and stimulates a patient’s immune system. The process begins with the selective infection of tumor cells. Viruses used in this therapy are chosen or engineered to preferentially target cancer cells, which often possess weakened antiviral defenses compared to healthy cells. This vulnerability allows the virus to enter the cancer cell and take over its internal machinery.
Once inside, the virus rapidly replicates, turning the cancer cell into a factory for producing more viral particles. This replication process consumes the cell’s resources and ultimately leads to its rupture, an event known as oncolysis. The bursting of the cell releases a new wave of virions, which can then infect and destroy adjacent tumor cells, propagating the anti-cancer effect throughout the tumor.
The destruction of cancer cells also triggers a secondary effect by activating the host’s immune system. When the infected cells burst, they release a variety of signals, including tumor-associated antigens (TAAs), which are proteins specific to the cancer. These signals, along with viral components known as pathogen-associated molecular patterns (PAMPs), act as alarms that draw the attention of immune cells. Antigen-presenting cells (APCs) collect these tumor antigens and present them to T-cells, training the immune system to recognize and attack the cancer throughout the body.
Types of Oncolytic Viruses
The viruses used in oncolytic therapy fall into two main categories: those that are naturally cancer-fighting and those that have been genetically engineered. Some viruses, such as the reovirus and Seneca Valley virus, inherently possess the ability to preferentially infect and kill cancer cells without modification.
Many oncolytic viruses used in clinical settings are genetically modified to improve their performance and safety. Engineering allows scientists to enhance a virus’s ability to target tumors while reducing its capacity to harm healthy tissues. For example, a virus can be altered to only replicate in cells that lack a specific tumor-suppressor gene, like p53, which is frequently mutated in cancers. This modification makes the virus highly selective for cancer cells.
Herpes Simplex Virus (HSV) and Adenovirus are two of the most common platforms for engineered oncolytic therapies. Talimogene laherparepvec (T-VEC), an approved therapy for melanoma, is derived from HSV. It has been modified to be less harmful to normal cells and to produce a molecule called GM-CSF, which helps stimulate the immune system. Similarly, adenoviruses have been engineered, such as the H101 virus approved in China for head and neck cancer, to selectively target and destroy malignant cells.
Administration and Application in Treatment
The delivery of oncolytic viruses to tumors is performed through precise methods. The most common approach is direct intratumoral injection, where the virus is delivered with a needle into a visible and accessible tumor, such as a melanoma lesion on the skin. This method concentrates the therapy at the site of the cancer, initiating a localized infection and immune response.
Another method of delivery is intravenous infusion, where the virus is administered into the bloodstream. This approach is necessary for treating cancers that are metastatic or not easily accessible for direct injection. Traveling through the circulatory system presents challenges, as the patient’s immune system may neutralize the virus before it reaches the tumor. Researchers are developing strategies to protect the viruses during transit to improve the effectiveness of systemic delivery.
Currently, the primary approved oncolytic virus therapy in the United States and Europe is talimogene laherparepvec (T-VEC). The U.S. Food and Drug Administration (FDA) approved T-VEC in 2015 for the treatment of advanced, inoperable melanoma. Beyond melanoma, numerous other oncolytic viruses are being evaluated in clinical trials for a range of cancers, including glioblastoma and bladder cancer. In 2022, the FDA also approved nadofaragene firadenovec-vncg, an adenovirus-based therapy, for certain types of non-muscle invasive bladder cancer.
Role in Combination Therapies
Oncolytic viruses are increasingly being used in conjunction with other cancer treatments, particularly immunotherapies. Their ability to change the tumor microenvironment is a primary benefit. Many tumors are considered immunologically “cold,” meaning they are not recognized by the immune system and are therefore resistant to immune-based treatments like checkpoint inhibitors.
By infecting tumor cells and causing them to burst, oncolytic viruses create an inflammatory environment. This influx of immune activity turns a “cold” tumor into a “hot” one, making it visible and susceptible to attack by the patient’s own immune system.
This synergistic effect is why oncolytic viruses are often paired with checkpoint inhibitors. Checkpoint inhibitors work by releasing the brakes on the immune system, allowing T-cells to attack cancer more effectively. When an oncolytic virus makes a tumor “hot,” it primes the cancer for a more robust response to the checkpoint inhibitor, improving therapeutic outcomes. This combination strategy is a focus of ongoing cancer research.