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Reviving exhausted T cells gets them back in the fight against cancer

Reviving exhausted T cells get...
Researchers have found a mechanism by which T cells become "exhausted" fighting cancer – and potentially uncovered a way around it
Researchers have found a mechanism by which T cells become "exhausted" fighting cancer – and potentially uncovered a way around it
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Researchers have found a mechanism by which T cells become "exhausted" fighting cancer – and potentially uncovered a way around it
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Researchers have found a mechanism by which T cells become "exhausted" fighting cancer – and potentially uncovered a way around it

One of the most promising emerging cancer therapies is CAR T cell immunotherapy, where a patient’s own immune cells are supercharged to fight tumors. Now researchers have found a way to refresh exhausted immune cells and get them back into battle sooner.

Our natural first line of defense against illness is our immune system, which uses T cells to patrol the body constantly on the lookout for proteins associated with specific pathogens, such as bacteria or tumor cells. As effective as this system is, sometimes it needs a little help.

Enter CAR T cell therapy. This intriguing treatment involves extracting a patient’s T cells, genetically engineering them with molecules tuned to cancer, and returning them to the body. Once there, they can get to work hunting down tumors with improved precision.

This therapy has shown some remarkably effective results in clinical trials, but so far it only really works in blood cancers like leukemia and lymphoma. Solid tumors have proven more difficult, because the CAR T cells tend to become “exhausted” in that environment.

Finding a way to prevent that exhaustion inspired the new study, led by researchers at University of Texas Southwestern. The team identified a gene called Cbl-b, which in previous studies appeared to be more active in exhausted T cells.

To test it out for themselves, the researchers studied T cells in mice with colon cancer, and found that they did indeed have higher levels of Cbl-b when they became exhausted. This state was also associated with a certain set of surface proteins, the inability to express other important molecules, and of course, a reduced tumor-fighting ability.

Importantly, when the team removed Cbl-b in those cells using CRISPR, they were able to attack the cancer effectively again. In another round of tests, the researchers genetically engineered mice that lacked Cbl-b, then implanted cancer cells into them. In these animals, the tumors grew smaller than they did in control mice.

Finally, the researchers deleted the Cbl-b gene from extracted T cells during the usual CAR T cell therapy process, and found that when they returned them to the mice, the cells were much more effective at fighting off cancer. The treatment seemed to prevent exhaustion.

“Our study is a major step forward in developing CAR-T cells to fight solid tumors,” says Venuprasad Poojary, lead author of the study. “This could overcome the limitations of some current immunotherapy strategies for cancer.”

As promising as these results may be, there’s still plenty of work left to do before this treatment could ever make it to humans. For one, the team says that understanding the exact molecular mechanism for how Cbl-b causes T cell exhaustion is a key step for future work.

The research was published in the Journal for Immunotherapy of Cancer.

Source: UT Southwestern

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