While doing a gel electrophoresis lab in my biology class, my teacher mentioned something about how even though viruses are not technically alive, they are very good at taking over human cells. That idea stayed with me, especially when I started reading about glioblastoma, one of the most aggressive types of brain cancer. Glioblastoma is extremely difficult to treat. Even after surgery and chemotherapy, the median survival is just 14-15 months. One reason for this is that glioblastoma cells can spread into healthy brain tissue around the tumor, so trying to remove every cell could damage important parts of the brain.
While reading about treatments, I came across an experiment where researchers used a modified version of poliovirus to treat brain tumors. Using a life-threatening virus to treat cancer was very strange to me. Poliovirus infects cells by attaching to the CD155 receptor, also known as the poliovirus receptor. Most normal brain cells have relatively low levels of CD155, but glioblastoma cells have much higher levels of the receptor. CD155 is associated with processes important to cancer cells for growing and interacting with the immune system.
This creates an opportunity. Because poliovirus naturally recognizes CD155, researchers realized that a modified poliovirus might be able to target glioblastoma cells. The biggest challenge was making the virus safe enough to use in the brain. Researchers at Duke University, including Dr. Matthias Gromeier, developed a modified poliovirus called PVSRIPO. They started with the weakened Sabin type 1 poliovirus vaccine strain. They then changed an important part of the virus’s RNA called the Internal Ribosome Entry Site, or IRES.
The IRES helps the virus use a cell’s protein-making machinery to reproduce itself. Researchers replaced the poliovirus IRES with one from human rhinovirus type 2, a virus associated with the common cold. This change greatly reduces the virus’s ability to damage normal nerve cells while still allowing it to function in certain cancer cells. Once PVSRIPO enters a glioblastoma cell through the CD155 receptor, it can reproduce inside the cancer cell. This damages and eventually kills the tumor cell.
What was even more interesting is that PVSRIPO may do more than just killing the cancer cells. Glioblastoma can be difficult for the immune system to recognize and attack, but when virus-infected tumor cells are damaged, they release tumor proteins and inflammatory signals. These signals can attract and activate immune cells. Dendritic cells can pick up material from the damaged tumor cells and help activate T-cells, including CD8+ T-cells, which can attack cancer cells.
A Phase 1 clinical trial at Duke studied PVSRIPO in 61 patients with recurrent glioblastoma. The virus was delivered directly into the tumor through a catheter. The median overall survival was 12.5 months among patients treated with PVSRIPO, compared with 11.3 months in a historical comparison group. Though the difference may not seem large, the long-term results held more promise. At 36 months, about 21% of patients treated with PVSRIPO were still alive, compared with about 4% in the historical comparison group. The survival curve for the PVSRIPO group reached a plateau, meaning that a smaller group of patients survived much longer than normally expected with recurrent glioblastoma.
However, the treatment is not 100% safe. PVSRIPO causes inflammation inside the tumor, which can lead to swelling in the brain. Because the skull cannot expand, severe swelling can become dangerous. Patients sometimes need additional treatment, including drugs such as bevacizumab, to control this problem.
There are also legal and regulatory questions involving clinical trials and expanded access to experimental treatments. “Right to Try” laws have added another way for some seriously ill patients to seek investigational therapies, but physicians and researchers still have responsibilities to explain the risks and determine whether treatment can be given safely.
There are also interesting intellectual-property questions. PVSRIPO was developed by modifying a virus related to a vaccine that has been used around the world for decades. Developing a new cancer therapy from an existing virus raises questions about what parts of the technology can be patented and how new discoveries should eventually become available to patients.
Before reading about this research, I mainly thought of viruses as causes of disease. PVSRIPO showed me that biology is much more complicated than that. Poliovirus was once one of the most feared causes of paralysis, but now, a modified version of it is being studied as a possible way to help the immune system fight one of the hardest cancers to treat.
Citations
Brown, Michael C et al. “Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs.” Science translational medicine vol. 9,408 (2017): eaan4220. doi:10.1126/scitranslmed.aan4220
Desjardins, Annick et al. “Recurrent Glioblastoma Treated with Recombinant Poliovirus.” The New England journal of medicine vol. 379,2 (2018): 150-161. doi:10.1056/NEJMoa1716435
Gromeier, M et al. “Intergeneric poliovirus recombinants for the treatment of malignant glioma.” Proceedings of the National Academy of Sciences of the United States of America vol. 97,12 (2000): 6803-8. doi:10.1073/pnas.97.12.6803