Cancer-killing viruses

We learned last time that cancer cells are cells whose DNA has been damaged beyond repair. Somatic mutations have accumulated to the point that the cell regulatory mechanisms no longer function, causing uncontrolled growth and proliferation. Despite being anomalous, cancer cells are still part of what the immune system recognizes as "self", which makes finding a cure for cancer such a hurdle. Therapy, when available, is often invasive and debilitating because the only way to make sure that all cancer cells in the body are destroyed is to stop all cells, even healthy ones, from growing. Drugs targeted at the tumor tissue only are a good alternative, though they still need to be perfected. Another way to overcome the hurdles is to train our immune system to recognize cancer cells and destroy them. In the past, I've discussed ways to do this through gene therapy and cancer vaccines.

So when my friend Mike Martin sent me this story, I thought, "Nice. Another cancer vaccine success story." As I read through, though, I realized that this wasn't quite a vaccine. It was a deadly virus turned into a "good" virus.

This is the story of the "redemption" of the poliovirus. :-)

Viruses hijack cell machinery (proteins) in order to reproduce. They do so because first of all, they are very small and they can't possibly package all the proteins they need into their tiny shell. Also, by using the cell's proteins instead of viral ones they disguise themselves: less viral proteins means more chances to evade the host immune system. When successful, most viruses end up killing their host cell.

What if we could do the opposite? What if we could hijack the viral proteins, instead, and use their "killing" machinery to ... kill cancer cells? That's the brilliant idea Dr. Matthias Gromeier, from Duke University had, and the basis of his research on oncolytic viral immunotherapy.

An oncolytic virus is a virus that targets cancerous cells. The term was coined after reports of cancer remissions that coincided with a viral infection or a vaccination. While in vitro models had originally given good results, the in vivo use of oncolytic viruses has shown to be more challenging than originally anticipated due to the complicated relationship between a virus and its host. One thing that makes the immune system so fascinating and yet so complicated to study, is that it depends not only on genetics ("innate immunity", the immunity we are born with), but also on "experiences" and "exposures" ("acquired immunity," the immunity that results from exposure to pathogens and immunogens throughout our lifetime), which are often much harder to reconstruct and fold into a model. So, whenever you try to use a virus for therapy, as in viral vectors for gene therapy, for example, you face the obstacle of different immune systems, some of which may have encountered the virus (or a similar one) before and will promptly destroy it.

In a 2011 paper [1], Gromeier and his group described PVSRIPO, a prototype nonpathogenic poliovirus they designed to treat glioblastoma, one of the most common and most aggressive brain tumors. The prototype is a poliovirus recombinant engineered to replicate exclusively in malignant cells. It targets one protein in particular, Necl-5, a tumor antigen expressed by many tumor cells. Think of it as a red flag that the tumor cells carry. PVSRIPO is able to "see" the red flag and attack the cell, eliciting "efficient cell killing and secondary, host-mediated inflammatory responses directed against the infected tumor [1]." In other words, not only it kills the cell, it also elicits immune responses against the affected area.

The prototype has been FDA-approved and is currently being tested in clinical trials with patients with glioblastoma multiforme, though it already made news:

"Of the seven others who later enrolled in Dr. DesJardins' clinical trial, one patient responded like Lipscomb [whose brain tumor is shrinking and has survived cancer for a year and a half, four times longer than most people with her type of tumor]. Two patients, whose immune systems were already severely damaged, did not. It’s too early to tell with the remaining three patients, but animal studies suggest that once the body recognizes and destroys the tumor, it won’t return. If those results hold up, researchers hope to apply the same technique to a whole range of other cancers, including melanoma and prostate cancer [2]."

[1] Christian Goetz, Elena Dobrikova, Mayya Shveygert, Mikhail Dobrikov & Matthias Gromeier (2011). Oncolytic poliovirus against malignant glioma Future Virology DOI: 10.2217/fvl.11.76