Tailor made viruses for enhanced cancer therapy

Parvoviruses specifically kill cancer cells and are already in the clinical trial stage for treating malignant brain tumors. However, they can also infect normal cells — without doing any harm to them — so a large portion of viruses is lost during therapy.
Scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now modified parvoviruses in such a way that they initially lose their ability to infect cells. In a second step, they equipped the viruses with a molecular key for infecting cancer cells.
A number of parvoviruses are able to enter and destroy cancer cells, while they do not cause any disease symptoms in humans. Since 1992, scientists working with Professor Jean Rommelaere at DKFZ have been studying such viruses with the aim of using them for cancer therapy.
For their studies, the researchers chose H1 parvoviruses, which normally infect rodents but are also infectious for human cells. H1 viruses kill tumor cells on the basis of their natural properties, i.e., their genetic material does not need to be modified for them to do so. At Heidelberg University Hospital, a phase I/IIa clinical trial is already ongoing to test treatment of malignant brain tumors using H1 viruses.
“The viruses exclusively destroy cancer cells. But with the same efficiency that they infect cancer cells, they also infect healthy cells. There they do not cause any damage and cannot replicate, but we lose a large portion of therapeutic viruses every time,” says Rommelaere. To solve this problem, the researchers engineered a virus. They first modified the genetic material of the virus in such a way that it loses its ability to infect cells. In a second step, this non-infectious virus was equipped with a molecular key for cancer cells.
Using a computer-based model of the H1 viral protein shell, Antonio Marchini and colleagues from Rommelaere’s department were able to make out how the virus makes contact with cells: It attaches to cell surface proteins that are linked to sialic acid. The researchers then exchanged two amino acids of a viral protein which are instrumental for contact with sialic acid.
This minute modification dramatically reduced H1′s capacity to infect cells: In cells treated with the genetically engineered virus, the investigators found not even a tenth of the virus load that would have been expected after infection with unchanged H1.