If you spend any time with people in retirement homes, they will sometimes tell you stories about their childhood and the dreaded “summer plague” known as polio. During the summer, children would go to ponds and lakes to swim in order to cool off from the summer heat. In those bodies of water, polio viruses would lurk, waiting to infect their new host. In most cases, infected people would experience a very flu-like disease that never went any further. In other cases, the flu-like disease might be more severe. Even in these people, the virus would be shed from the body by the digestive system and contaminate sewage water.
In rare cases, the central nervous system would be affected, but the aftermath of the disease would vary substantially. Some might some numbness for a little while. In a fraction of cases, they might actually experience paralysis that did not go away. The extent of this paralysis could vary tremendously. In some cases, people might retain the ability to walk, but with a limp. In other cases, they might not be able to walk at all. And in more severe cases, they might lose the ability to breathe on their own and require an iron lung to breathe for them. Polio struck young and old, male and female, rich and poor alike and was no respecter of persons.
The polio vaccines made by Jonas Salk (a formalin-killed vaccine) and the live vaccine made by Albert Sabin essentially eradicated polio in many countries and saved untold of millions of lives from suffering. In fact, Albert Sabin gave away the rights to his vaccine even though those rights could have made him a millionaire. Because his live vaccine could be given in a sugar cube, it was extremely easy and inexpensive to administer to large populations.
Given this history, why would clinicians reinstate a deadly virus to fight cancer? The answer is that polio viruses is a highly lytic virus, but it can be genetically manipulated to specifically attack cancer cells.
First a bit about the molecular biology of polio virus. Polio virus is a member of a group of RNA viruses called the “picornaviruses.” The name of this group comes from “pico” meaning small, “RNA” to refer to the type of nucleic acid found in the virus, and the virus to indicate the type of infectious agent that it happens to be. Viruses are nucleic acid molecules encases in a protein capsid. When ingested from contaminated water by drinking or simply putting your hands in your mouth, the polio virus binds to a cell surface protein called CD155 found in the intestinal walls. It enters these cells and uncoats. The RNA genome of the polio virus is then translated by ribosomes in the cell into a large protein. This is a key feature of picornaviruses; their viral RNA genomes can serve as messenger RNAs that are directly translated into protein right after emerging from their capsids.
This large protein has the ability to process itself. That processing comes in the form of clipping pieces of the protein into small pieces. These smaller pieces have specific functions. The first pieces are creatively called P1, P2 and P3 (you have to love those biochemists and their ability to dream up creative names – yes that was a joke). Eventually, the viral proteinases (enzymes that clip proteins) 2A and 3C further process these three precursor proteins to form the viral capsid proteins VP1-4 (formed from P1) and the viral replication proteins 2A, 2B, 2C (formed from P2), 3A, 3B, 3C, and 3D (formed from P3). As mentioned before, 2A and 3C are proteinases, 3B is a protein called VPg, and 3D is RNA-dependent RNA polymerase that replicates the viral RNA into copies that are packaged into viral capsids.
The whole infection process is insidiously effective because there is a piece of RNA at the very front of the poliovirus genome called the IRES, which stands for the internal ribosome entry site. This sequence of 400 to 500 bases directs the viral translation initiation step in a manner independent of whether or not there is a special cap-structure on the front end of the RNA. It allows poliovirus RNAs to be effectively recognized by the host cell and the cell’s own mRNAs to not be well-recognized because the polio 2A protease degrades elements of the cell’s own translation machinery, which prevents the cell from recognizing its own mRNAs.
As it turns out, if you swap this IRES with IRESs from other types of viruses, you can change the types of cells that polio virus will infect. In 2000, Eckard Wimmer and his group from the State University of New York at Stony Brook showed that substituting the polio virus IRES for that of the IRES from the common cold virus (Rhinovirus) allowed poliovirus to grow in cultured brain tumor cells (see Gromeier M, et al., Proc Natl Acad Sci U S A. 2000, 97(12): 6803–6808). Since these tumors expressed CD155, the receptor for poliovirus, they could be infected with it. Wimmer and his team made attenuated strains of these viruses and used them in non-human primates that had brain tumors. When injected directly into the tumor, the viruses infected only the tumor cells, and grew poorly, but the immune response against the virus and the infected cells caused the tumors to aggressively shrink.
So Gromeier and his team collaborated with neuro-oncologists to use their engineered polio viruses to treat human patients with glioblastomas. These are very aggressive cancers that usually end up killing the patient. in a clinical trial, of 22 people enrolled in the trial, half are doing well, and several are considered to be in remission, which is pretty much unheard of for glioblastomas.
The news show 60 Minutes even did a piece on this treatment and interviewed two patients with aggressive glioblastomas were treated by this polio virus. Their tumors have essentially disappeared. In fact, the first person who was ever treated with this treatment is now cancer free.
While this is a small study, it was supposed to be a Phase I study that only determined safe dosages and safety parameters. you do not expect patients to improve much in Phase I studies because you are still tweaking the treatment. These results are astonishing. Also, because it uses the patient’s own immune response against the infected cells it does not depend on massive alterations of the patient’s physiology.
This is a remarkable finding. I hope it can be developed into something mainstream that turns out to be safe and effective.