“Weaponized” CAR T cell therapy shows promising results against solid tumors

Immune cells genetically engineered to kill cancer cells, known as CAR T cells, have revolutionized the treatment of blood cancers such as leukemia, but have proven largely ineffective against solid tumors. But now, “weaponized” CAR T cells have been able to eliminate large solid prostate tumors in mice, raising hopes that this approach will work against all types of cancer in humans.

“The tumors were gone, completely gone,” he says. Jun Ishihara At Imperial College London. He says this is the first time such results have been achieved in an animal study.

Our immune system kills many types of cancer before they become a problem. Mutated proteins on the surface of cancer cells are recognized as foreign, and immune cells known as T cells are sent to eliminate them. These cells trap by touch, identifying cancer cells using receptor proteins on their surfaces that – like antibodies – bind to the mutant proteins.

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

CAR T cells can have serious side effects and It doesn’t work for everyonebut it has effectively treated blood cancers in some people, and is constantly being improved. In particular, the advent of CRISPR gene editing technology has made it easier to make additional modifications to CAR T cells that make them more effective.

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

So researchers tried to use CAR T cells as a weapon by making them produce powerful immune-stimulating proteins, such as interleukin 12. But these treatments have proven to be too powerful, making the immune response so strong that it damages many healthy tissues.

Now, Ishihara and his colleagues have found a way to localize IL-12 in tumors. They first combined interleukin with part of the protein that binds to collagen. Interleukin normally seeks out exposed collagen in injured blood vessels to aid healing, but tumors have been shown to resemble wounds in the presence of exposed collagen, Ishihara says. “The tumors have a lot of collagen. They are firm and firm because of the collagen.”

Next, the team modified the CAR T cells so that the fusion protein was produced after these T cells bound to a mutated protein found in some prostate cancers. Once released, the protein fused to collagen within tumors must bind and remain localized, with the interleukin 12 moiety effectively screaming, “Attack! Attack!”

In tests, the treatment completely eliminated large prostate tumors in 4 out of 5 mice. When the mice were later reinjected with cancer cells, they did not develop tumors, showing that the CAR T cells had elicited an effective immune response.

The mice also did not need any kind of preconditioning. Typically, chemotherapy is used to kill some of a person’s existing immune cells before treatment with CAR T cells to “make room” for the added cells. This could be it Side effects, such as affecting fertility. “We were actually surprised that we didn’t need chemotherapy at all,” says Ishihara. His team hopes to begin clinical trials in humans within two years.

“I think this is a promising approach that should be tested clinically,” he says. Stephen Albelda At the University of Pennsylvania in Philadelphia. A number of other groups are also working on ways to localize IL-12 in tumors, Albelda says, some of which have also It had promising results.

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