Herpes on the brain could be a good thing?

herpes-on-the-brainWhat do these two odd pairings have in common? Cervical cancer and rabies vaccination. Hodgkin’s lymphoma and measles.

The answer is that they are both among the earliest case reports, as early as 1901, linking spontaneous remission of a cancer with a virus. These discoveries led to idea of using viruses to kill cancer cells, so-called ‘oncolytic viruses’.

It’s a neat idea. If you can get a virus to preferentially infect tumour cells, leaving normal cells and tissue alone, as it destroys the tumour cells more infectious virus is released to go on and infect the remaining tumour cells. In fact, it’s such a neat idea that there are currently a number of oncolytic viruses going through clinical trials right now.

But it’s not just through infection, replication and destruction of cells that a virus can kill a tumour. A virally infected cell can jump-start the immune system, bringing attention to tumour cells which had otherwise evaded the immune system, generating an anti-tumour immune response.

However, the immune system can also be a hurdle for using oncolytic viruses as a therapy. After all, preventing and combating viral infection is one of the immune systems jobs. One way to get past this, or minimise it, is to deliver the oncolytic viruses directly to where they’re needed, the tumour site, and keeping them there.

Keeping oncolytic viruses where they’re needed has been an issue in clinical trials aiming to treat glioblastoma multiforme (GBM). GBM is the most common brain tumour in human adults, and one of the hardest to treat. Treatment of GBM usually involves surgery to remove as much tumour as possible, followed by radio or chemotherapy.

Micrograph showing the viral cytopathic effect of HSV (multi-nucleation, ground glass chromatin).

Micrograph showing the viral cytopathic effect of HSV (multi-nucleation, ground glass chromatin).

Oncolytic herpes simplex viruses (oHSV) have been considered especially promising for treating GBM, since they naturally infect dividing nerve and brain cells. Clinical trials with oHSV have shown some anti-tumour activity, but have been considered disappointing, as they didn’t persist long enough to work well.

One possible reason for this is that bleeding and cerebrospinal fluid at the surgery site can rinse out the virus once injected at the site. One way around this problem, and to avoid antiviral immune responses, is to use a Trojan horse.

Researchers from the Harvard Stem Cell Institute (HSCI) recently published a paper doing just this. The team loaded up mesenchymal stem cells (MSCs) with oHSV, to smuggle them into them into tumour sites in a mouse model of GBM and assess their effectiveness. They also coated the infected MSCs in a synthetic extracellular matrix, a kind of biological gel, and injected this directly into the tumour site.

The virus particles were also loaded up with genes imaging proteins, such as firefly luciferase, a bioluminescent protein. This allowed the team to monitor, in real time, how the virus spread through the tumour site killing the cancer cells. They found that mice injected with the gel-encapsulated MSCs had a higher survival rate than controls mice, including those injected with the oHSV alone.

“They survived because the virus doesn’t get washed out by the cerebrospinal fluid that fills the cavity,” Said Dr Khalid Shah, who led the work, in a press release. “Previous studies that have injected the virus directly into the resection cavity did not follow the fate of the virus in the cavity. However, our imaging and side-by-side comparison studies showed that the naked virus rarely infects the residual tumour cells. This could give us insight into why the results from clinical trials with oncolytic viruses alone were modest.”

However, not all brain tumours are susceptible to therapy with oncolytic viruses. To address this issue the researchers engineered oHSV to include a gene for a protein called TRAIL, protein which promotes apoptosis – cell suicide. They then tested this in the same GBM mouse model, but this time using tumour cells already resistant to HSV. Again, they found that this increased animal survival compared to control animals.

As with all such pre-clinical work, it should be stressed that these results might not transfer easily in to humans. However, Shah estimates that their approach of encapsulating virus loaded cells to treat brain cancer could enter clinical trials within the next two to three years.

You can find more information on virology on our site.

Source: Duebgen, M., Martinez-Quintanilla, J., Tamura, K., Hingtgen, S., Redjal, N., Wakimoto, H., & Shah, K. (2014). Stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy. Journal of the National Cancer Institute, 106(6), 1–9. doi:10.1093/jnci/dju090

 

Image credits:

HSV micrograph: wikipedia

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