Cancer cells do a pretty good job of flying under the radar of our immune system. They don't raise the alarm bells signaling they are a foreign invader the way viruses do. That might be something scientists can change, though.
A team of researchers has built non-infectious artificial viruses containing proteins found in cancer cells. The designer viruses don't cause infections but do train the immune system to see the cancer proteins as a threat and react to them.
Using viruses to help kill cancer cells is not new, but engineering viruses so that they activate specific components of the immune system to create a precise and targeted response to cancer cells is a new and rapidly evolving science.
The new lab-made virus would serve several purposes. It would provoke the immune system to respond to it as foreign material in the body and carry a bit of cancer protein that could direct the immune response at cancer cells.
The researchers had to integrate the cancer cell proteins into the engineered virus to stimulate the immune system into action against the tumor. The scientists wanted large numbers of CD8 T lymphocytes activated because they are the killer cells of the immune system and would attack the tumor. Other research has shown that people with cancer survive longer if killer T cells infiltrate their tumors.
At the same time, the scientists wanted their cancer protein-bearing virus to help the immune system create a pool of memory T cells. Those memory T cells would retain a memory of fighting the cancer cells and sit, ready to respond should they encounter and recognize the same cancer cells again.
More virus would mean a bigger immune response, so the virus would have to be genetically modified so that it would not produce disease, but could still replicate. The researchers chose to pattern their artificial virus after lymphocytic choriomeningitis virus, a virus that multiplies by entering cells and integrating their genetic material with that of the host cell. That way, the host cell would make more of the virus, using the host's cellular resources and normal processes. New viral particles leave the cell and go on to infect other cells, a process that would be used to replicate the engineered virus.
Usually, but not always, the process of viral particle replication kills the host cell when the newly-produced virus leaves the cell. These types of virus are called cytolytic, or cell-bursting. It was desirable for the engineered virus to be "non-cytolytic" because it was important to multiply the virus, but not kill healthy host cells it infects.
Replicating viruses can generate a stronger immune response because they mimic a natural infection. The scientist believed that by using virus capable of reproducing, more virus would be available to travel throughout the body to initiate immune responses — strong immune responses — wherever the cancer cells were located.
The researchers chose to use a virus called the Lymphocytic choriomeningitis virus for their engineered virus because it's a non-cytolytic virus known to generate both large numbers of killer T cells and high numbers of memory cells. Memory cells remain in the body for several years after a single infection with the virus, which could mean lasting protection against cancer.
Merkler and his team created their artificial virus from lymphocytic choriomeningitis virus, and integrated proteins found only in cancer cells. The tumor-specific proteins allowed the immune system to recognize these cancer proteins as foreign and mount a response to them.
Interleukin 33 is a protein elicited from cells of the immune system and is critical to generating the robust response of killer T cells. When the researchers injected mice with the artificial virus, the mice released Interleukin 33 in response, but they didn't release it against to a virus that had been rendered incapable of multiplying.
Nine days after researchers injected the mice in the flank with tumor cells, they were given the engineered virus intravenously. The researchers measured the volume of the developing tumors using calipers. The tumors grew slightly in mice given the artificial virus but stopped growing after about three days. Tumors in mice who did not receive the virus increased in size by about 6-fold in 20 days, and all those mice were dead in 30 days. Thirty days after injection with the virus, about 35% of the infected mice were still alive. When the experiment ended 40 days after injection of virus, about 20% were still alive.
The virus did not cause a disease in mice but did activate the immune system to sound the alarm that cancer cells were present. When Interleukin 33 was released, it called a barrage of CD8 killer T cells to the tumor to kill the cancer cells. Of course, many factors besides CD8 cells determine whether cancer cells live or die, but researchers have noted in the past that higher numbers of cytotoxic (killer) T cells at the site of tumors predict increased survival in human cancers. The numbers of these T cells in the mice and the death of cancer cells they caused likely drove the increased survival rate seen in the mice treated with the engineered virus.
Knowing what components of the immune system they wanted to activate allowed researchers to design a custom virus that stimulated the immune system to react to cancer cell proteins in specific and precise ways. While the virus didn't stop the mice from dying, it did significantly slow tumor growth and delayed death. The artificial virus has already been patented, and the study authors hope that this virus, or a better version of it, can eventually be used to treat human cancers. This artificial virus prototype is only the beginning of what we can accomplish can with designer virus technology.
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