Genetically Modified Adenovirus—New Weapon Against Metastatic Cancer

Nowadays, metastatic cancer has been facing an overwhelming obstacle, that is, the human immune system. In a new study, the researchers redesigned the human adenovirus so that the virus is not easily captured by a part of the innate immune system. This makes it possible to inject the virus into the blood without causing a large-scale inflammatory response. The study reported the cryo-EM (cryo-EM) structure of this redesigned virus, and also reported that it can eliminate disseminated tumors in mice.

When viruses are injected intravenously, the innate immune system delivers them to the liver very efficiently. For this reason, most oncolytic viruses are delivered directly into the tumor without affecting the metastatic tumor. In contrast, if it is possible to deliver the modified virus systemically in a high enough dose to inhibit tumor growth without causing life-threatening systemic side effects.

Adenovirus is also the core of gene therapy research. The current focus of research is to redesign adenovirus, this delivery system has been used in dozens of cancer clinical trials to stimulate the host's anti-tumor response. The redesigned adenovirus is a platform technology that can be adjusted and customized for multiple types of cancer, and even can be customized for a single cancer patient.

Researchers published a study report on how the adenovirus interacts with a host factor in the blood-coagulation factor X-by cryo-electron microscopy. Researchers claim that even small changes in structural proteins can be catastrophic and prevent the assembly of infectious viruses. In this case, they modified the adenovirus in three places to minimize the interaction of this virus with specific blood factors. In the end, it was discovered that this virus can still assemble and maintain the function of infecting and killing tumor cells. It is still possible to form a slower-established adaptive immune response to the modified adenovirus, similar to the situation observed after vaccination. A group of viruses can be used for continuous administration to cancer patients to prolong the therapeutic effect.

The study found for the first time that it can modify the combination of natural IgM and adenovirus, introducing mutations that prevent the virus from inactivating in the blood and preventing it from being captured by liver macrophages. Liver macrophages are the largest pool of immune cells in the human body to capture and destroy pathogens. The researchers also replaced the part of the adenovirus that interacts with the integrin of human cells and replaced this part with another human protein---the laminin alpha 1 (laminin-) that targets the virus to tumor cells.?1) --- sequence. Thus, the high-resolution cryo-EM structure of this redesigned adenovirus was obtained.

When injected into mice, high doses of standard adenovirus can cause liver damage and death within a few days, but this redesigned adenovirus does not. This redesigned adenovirus can eliminate disseminated tumors in some mice transplanted with human lung cancer cells, but it cannot eliminate tumors in all mice: about 35% of the mice have a complete response and there is no detectable The survival time of the tumors reached has also been prolonged. These researchers found that the tumor sites in the lungs were transformed into scar tissue. At present, the laboratory is exploring ways to further increase the proportion of complete responders.

Clinically, metastatic lung cancer will be the most suitable type of cancer to test the efficacy of oncolytic viruses. This technique can also be used for gene therapy applications.

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