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Evading exhaustion to improve CAR-T cell therapy

'Resting' exhausted cancer-fighting immune cells enhances their tumor-killing activity, which may help people with blood and solid cancers.

Even cells need a rest sometimes. In 2017, I had the privilege of writing about what was then a relatively new therapy for leukemia called CAR-T cell therapy. The therapy uses a patient's own genetically modified T cells (a kind of immune cell) to seek out and attack cancer cells, and it's been remarkably successful in many cases. Since then, it's been approved to treat certain types of lymphomas, as well as the blood cancer multiple myeloma.

But the cells' cancer-killing efficiency often wanes over time -- a result of them becoming exhausted from being always "on." It's thought that this exhaustion is a natural safety feature to guard against overzealous immune responses that can cause autoimmune disorders. But it limits the effectiveness of the promising treatment against solid tumors, which require a sustained attack, and means that some blood cancer patients have to seek other treatments to cure their disease.

Now instructor Evan Weber, PhD, and oncologist Crystal Mackall, MD, have found that giving the cells a brief rest resets their cancer-killing ability. They published their findings recently in Science.

Rest, reset, repeat

Weber, Mackall and their colleagues discovered the power of rest when thinking about another complication of CAR-T cell therapy. In some patients, administration of the genetically modified T cells cause a potentially life-threatening phenomenon called a cytokine storm -- an overproduction of molecules that regulate inflammation.

"We wondered if there were ways to regulate the activity of the CAR-T cells to mitigate the toxicity of the treatment," Weber said. Then they wondered whether toggling the cells' cancer-fighting activity to allow a brief rest could help mitigate their exhaustion. "If we could just shut the cell off for a while, giving it a chance to rest and reset, would they function better when their activity was restored?" 

He and Mackall teamed up with chemical biologist Tom Wandless, PhD, to generate CAR-T cells with a destabilizing domain incorporated into the protein responsible for the cells' cancer-fighting ability. The effect of the destabilizing domain, which disrupts the production of the protein, called a chimeric antigen receptor, or CAR, can be reversed by treatment with a small drug molecule.

"In the absence of the drug, the levels of CAR protein rapidly decrease," Weber said. When the drug is reapplied to the cells, the CAR protein is again produced and the cells spring back into action.

While testing the newly modified CAR-T cells in mice, the researchers found that exhausted cells that were allowed to rest for as few as four days were much better at attacking and killing cancer cells. Animals with tumors that were treated with the rested CAR-T cells lived significantly longer than those that received a control treatment.

Better cells all around

The researchers found that the exhausted CAR-T cells used their rest time productively. In particular, they removed genetic tags on their DNA that accumulate during exhaustion -- tags that had previously been thought to be permanent.

"We were surprised to find not just a few changes but a whole-scale remodeling of the genome to resemble cells that had never been exhausted at all," Weber said. "This was really striking, and it signaled to us that we were profoundly changing some biological aspects of these cells.

"We found that even after a short rest period of about four days, the cells could kill cancer cells better. Also, they were again able to secrete signaling molecules called cytokines and proliferate," Weber said. "They looked like they were better cells all around."

Although the results are promising, there are some potential stumbling blocks. Turning off all the CAR-T cells in a patient could allow any remaining tumor cells to grow unchecked. To counteract that, it might be necessary to find ways to selectively turn off a subset of CAR-T cells at a time.

"Many groups are working to find ways to fine-tune CAR-T cell activity," Weber said. "Our study suggests one way to tune activity to make this treatment more efficacious for cancer patients."

By Volha

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