Immune cells as “hackers” treat cancer

CAR-T cells attack cancer cells. Image source: Science

Scientists have discovered that well-engineered immune cells not only recognize cancer cells, but also escape the tumor’s defense system against attack. Two related papers were published in Science on December 15.

The two studies build on the success of CAR-T cancer therapy. The therapy uses gene-edited T cells to find and label tumors for eventual destruction. Although this therapy can alleviate the disease, it has so far been effective against only a few cancers, and not for everyone.

To enhance the power of CAR-T therapy, the researchers further engineered the cells to contain “switches” that control when and where the cells move. “Hacker” cells produce a protein that stimulates T cells to counteract the immunosuppressive signals that tumors often release.

Grégoire Altan Bonnet, a systematic immunologist at the National Cancer Institute, said both studies are a direction in the field of T cell engineering and underscore the hope of researchers advancing CAR-T cell therapy.

“We know a lot of parts and now we can put them together and explore. If designed well, we can really destroy tumors. Bonnet said.

T cells usually “roam” the body, looking for foreign proteins displayed on the cell surface. For example, these cells may be infected with a virus, or they may be tumor cells that produce abnormal cancer-associated proteins. And “killer” T cells can destroy abnormal cells.

CAR-T therapy involves genetically engineering T cells from cancer patients. At present, this method has been approved for the treatment of some patients with leukemia, lymphoma and myeloma. But researchers have been looking for ways to make treatments safer and more effective, and expand their application to other diseases.

In one of the new studies, Boston University synthetic biologist Ahmad Khalil and colleagues connected a complex system of 11 DNA sequences to CAR-T cells, and the resulting gene circuit “switch” could be controlled by already approved drugs.

This allowed the researchers to control when and where T cells that were “hacked” to become active to get them to produce a protein called IL-2, which stimulates an immune response.

Another team of researchers, led by Wendell Lim, a synthetic biologist at the University of California, San Francisco, edited CAR-T cells to produce IL-2 only when the gene-edited T cells encountered cancer cells.

The team found that IL-2 was most effective against tumors in pancreatic cancer mice when activated via a different pathway than it recognizes cancer cells. This detail could help shape future treatments.

Andrea Schietinger, an immuno-oncologist at Memorial Sloan Kettering Cancer Center, said both approaches are particularly useful when developing CAR-T therapies that target solid tumors.

Solid tumors pose a particular challenge to the CAR-T approach because gene-edited cells have a hard time penetrating into tumors, and once they do, they are blocked by signals that cancer cells use to suppress immune responses.

“These gene-edited T cells overcome this hurdle.” Schietinger said, “They find a way in, and once they get in, they get signals in the right space and time to really kill cancer cells.” (Source: Wang Fang, China Science News)

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