‘Weaponised’ CAR T-cell therapy shows promise against solid tumours

Immune cells that were genetically modified to kill cancer cellsknown as CAR T cells, have changed the way blood cancers are treated for example leukemiabut were largely ineffective against solid tumors. But now weaponized CAR T cells have destroyed large solid prostate tumors in mice, raising hopes that this approach will work against all cancers in humans.

“The tumors have disappeared, completely disappeared,” says Jun Ishihara at Imperial College London. According to him, such results were achieved in an animal study for the first time.

Our immune system kills many cancers before they become a problem. Mutant proteins on the surface Cancer the cells are recognized as foreign and immune cells known as T cells are sent to destroy them. They hunt by touch, identifying cancer cells using receptor proteins on their surface that, like antibodies, bind to mutant proteins.

Unfortunately, not all cancers generate an immune response, but in the 1980s, biologists realized that it was possible to genetically modify T cells to target them. This is done by adding a gene for an artificial receptor protein known as a chimeric antigen receptor – hence the name CAR T.

CAR T cells can have serious side effects and don't work for everyoneBut they have effectively cured blood cancer in some people and are constantly being improved. In particular, the advent of CRISPR gene editing has made the task much easier. make additional modifications to CAR T cells which makes them more effective.

But despite all these improvements, CAR T cells have failed to combat the vast majority of cancers that form solid tumors. There are two main problems. First, solid tumor cells are usually very diverse and not all have the same mutant protein on their surface. Second, solid tumors are good at preventing immune attacks, for example by generating “don’t attack me” signals.

So researchers tried to weaponize CAR T cells by tricking them into producing powerful immune-stimulating proteins such as interleukin 12. But these treatments turned out to be too powerful, making the immune response so strong that it damaged many healthy tissues.

Now Ishihara and his colleagues have found a way to localize interleukin 12 in tumors. First, they combined interleukin with part of the protein that binds to collagen. “Interleukin typically looks for collagen found in damaged blood vessels to promote healing, but it turns out that tumors are similar to wounds in terms of exposing collagen,” Ishihara says. “Tumors have a lot of collagen. They're tough and hard because of the collagen.”

The team then modified the CAR T cells so that the fusion protein is produced after the T cells bind to a mutant protein found in some types of prostate cancer. Once released, the fusion protein must bind to the collagen inside the tumor and remain localized, with the interleukin-12 portion essentially screaming, “Attack! Attack!”

In trials, the treatment completely eradicated large prostate tumors in 4 out of 5 mice. When the mice were later reinjected with cancer cells, they did not develop tumors, suggesting that the CAR T cells triggered an effective immune response.

The mice also did not require any preliminary preparation. Chemotherapy is typically used to destroy some of a person's existing immune cells before CAR T-cell therapy to “make room” for the added cells. This may have side effects such as effects on fertility. “We were actually surprised that we didn’t need chemotherapy at all,” Ishihara says. His team hopes to begin human clinical trials within two years.

“I think this is a promising approach that should be tested clinically,” says Stephen Albelda at the University of Pennsylvania in Philadelphia. Albelda says a number of other groups are also working on ways to localize interleukin 12 to tumors. there were promising results.