The use of viruses to specifically target and destroy cancer cells, a field known as oncolytic virotherapy, represents a significant development in cancer research. This approach involves modifying naturally occurring viruses to make them harmless to healthy cells while retaining their ability to infect malignant ones. A specific example generating considerable interest is the polio virus vector, often referred to as PVS-RIPO, a genetically engineered version of the poliovirus vaccine. This novel immunotherapy leverages a well-known pathogen to deliver an anti-tumor response.
The Genesis of Polio-Based Therapy
The foundation of this treatment lies not in the naturally occurring wild poliovirus, but in a modified strain derived from the live-attenuated oral poliovirus Sabin type 1 vaccine (PV1S). Scientists at Duke University spearheaded the genetic alteration that transformed this virus into an oncolytic agent. The primary modification involved replacing a specific genetic element within the virus known as the Internal Ribosome Entry Site (IRES).
The native IRES of the poliovirus was substituted with the corresponding IRES from the human rhinovirus type 2 (HRV2), the common cold virus. This exchange effectively eliminated the virus’s ability to infect and replicate within healthy nerve cells, thereby removing its neurovirulence. The resulting recombinant virus, PVS-RIPO, maintains the ability to target cells that overexpress the poliovirus receptor, a molecule called CD155 or Necl5. This receptor is commonly found in high concentrations across many types of solid tumors, making it an ideal target.
Mechanism of Action Against Tumors
The therapeutic effect of the modified poliovirus operates through a two-pronged mechanism within the tumor microenvironment. The first action is a direct attack where PVS-RIPO selectively infects cancer cells due to the high expression of the CD155 receptor on the cell surface. Once inside, the virus replicates rapidly, overwhelming the cell’s machinery and causing the cancer cell to burst, a process called oncolysis or direct lysis. This destruction releases new viral particles to continue the cycle on neighboring tumor cells.
The second action is the activation of the patient’s immune system. When the cancer cells undergo lysis, they release tumor-specific antigens and molecular “danger signals” into the surrounding tissue. This influx of material draws the attention of the body’s immune cells, specifically T-cells and antigen-presenting cells. The poliovirus acts as an immunological adjuvant, teaching the immune system to recognize the previously hidden cancer cells as a foreign threat.
Current Status and Clinical Trial Results
The most advanced clinical investigation of PVS-RIPO has been in the treatment of recurrent Glioblastoma Multiforme (GBM), the most aggressive form of brain cancer. Standard treatment for recurrent GBM typically results in a poor prognosis, with a median overall survival (mOS) of approximately nine to eleven months. The promising preliminary data led the FDA to grant the therapy Breakthrough Therapy Designation in 2016, aiming to expedite its development.
In published Phase 1 and interim Phase 2 clinical trial results, PVS-RIPO demonstrated a prolonged survival benefit for patients with recurrent GBM. The median overall survival for treated patients was reported to be around 12.5 months, an improvement compared to the typical 11.3 months observed in historical control groups. The sustained long-term survival rates diverged notably from standard care after the first year. The overall survival rate for PVS-RIPO-treated patients reached 21% at both the two-year and three-year mark, a stark contrast to the 4% three-year survival rate seen in comparable control patients. While GBM remains the primary focus, the expression of the CD155 receptor on other malignancies has prompted early-phase trials in tumor types such as refractory melanoma, breast, and prostate cancer.
Patient Considerations and Next Steps
The administration of the poliovirus vector is localized for treating brain tumors. The treatment is delivered via a single, slow intratumoral infusion using a method called convection-enhanced delivery (CED). This process involves surgically implanting a thin catheter directly into the tumor mass, allowing the virus to be slowly and evenly distributed throughout the target area.
Because the therapy is designed to trigger an immune-inflammatory response within the tumor, the most common side effects observed are related to localized inflammation. These adverse events typically manifest as neurological symptoms due to peritumoral edema, or swelling, in the brain. Specific side effects can include hemiparesis, seizures, and lymphopenia.
These inflammatory effects are generally managed effectively through the use of low-dose corticosteroids or the drug bevacizumab, which helps to control the localized swelling. Patient eligibility for the trials requires a specific tumor type, such as recurrent GBM, and a suitable functional status. Researchers are now focused on advancing to a larger, potentially definitive Phase 3 trial to confirm these survival benefits and determine the final regulatory pathway for broader clinical availability.