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New vaccine strategy strengthens T cell therapy



A promising new way to treat certain types of cancer is to program the patient's own T cells to destroy the cancer cells. This approach, called CAR-T cell therapy, is now used to fight against certain types of leukemia, but so far, it has not worked well against solid tumors such as lung tumors or lung tumors. breast.

MIT researchers have devised a way to overload this treatment so that it can be used as a weapon against almost all types of cancer. The research team has developed a vaccine that dramatically increases the antitumor T cell population and allows cells to vigorously invade solid tumors.

In a study of mice, researchers found that they could completely eliminate solid tumors in 60% of animals that received T cell therapy at the same time as booster vaccination. Modified T cells have virtually no effect.

"By adding the vaccine, a life-saving CAR-T cell treatment can be amplified to give a complete response in more than half of the animals," says Darrell Irvine, professor Underwood-Prescott with appointments in Biological Engineering and Materials Science and Engineering, Associate Director of the Koch Institute for Cancer Research and Integration of Koch at MIT, member of the Institute Ragon of 39, HGM, MIT and Harvard and lead author of the study.

Leyuan Ma, MIT's postdoc, is the lead author of the study, which appears in the July 11, 2002 online issue. Science.

Target tumors

Until now, the FDA has approved two types of CAR-T cell therapy, both used to treat leukemia. In these cases, T cells extracted from the patient's blood are programmed to target a protein, or antigen, present on the surface of B cells. ("CAR" in CAR-T cell therapy is for "chimeric antigen receptor". )

Scientists believe that one of the reasons this approach has not worked well for solid tumors is that tumors usually generate an immunosuppressive environment that disarms T cells before they can reach them. their target. The MIT team decided to try to address this problem by providing a vaccine that would go to the lymph nodes, which harbor huge populations of immune cells, and stimulate CAR-T cells.

"Our hypothesis was that, if you stimulated these T cells via their CAR receptor in the lymph node, they would receive the right set of priming cues to make them more functional so that they could withstand at closing and would work when the tumor, "says Irvine.

To create such a vaccine, the MIT team used a trick discovered several years ago. They discovered that they could administer the vaccines more effectively to the lymph nodes by linking them to an adipose molecule called lipid tail. This lipid tail binds to albumin, a protein found in the blood, allowing the vaccine to move directly into the lymph nodes.

In addition to the lipid tail, the vaccine contains an antigen that stimulates CAR-T cells once they reach the lymph nodes. This antigen could be either the same tumor antigen targeted by T cells or an arbitrary molecule chosen by the researchers. In the latter case, the CAR-T cells must be reconfigured so that they can be activated by both the tumor antigen and the arbitrary antigen.

In tests on mice, the researchers showed that one or the other of these vaccines significantly improved the T cell response. Approximately 50,000 T-Cells were administered to mice, but none vaccine was found, but CAR-T cells were almost undetectable in the blood of animals. In contrast, when the booster vaccine was administered the day after T-cell infusion and again a week later, T-CAR cells developed to 65% of the total T-cell population of T-cells. animal, two weeks after treatment.

This dramatic increase in the CAR-T cell population resulted in the complete elimination of glioblastoma, breast tumors and melanoma in many mice. CAR-T cells administered without vaccine had no effect on the tumors, while CAR-T cells administered with the vaccine eliminated the tumors in 60% of the mice.

Long-term memory

This technique is also promising to prevent recurrence of the tumor, says Irvine. About 75 days after the initial treatment, the researchers injected tumor cells identical to those that formed the initial tumor, and these cells were eliminated by the immune system. About 50 days after that, the researchers injected slightly different tumor cells, which did not express the antigen targeted by the original CAR-T cells. the mice could also eliminate these tumor cells.

This suggests that once CAR-T cells begin to destroy tumors, the immune system is able to detect other tumor antigens and generate "memory" T-cell populations that also target these tumors. proteins.

"If we take the animals that seem to be cured and challenge them with tumor cells, they will reject them all," says Irvine. "This is another exciting aspect of this strategy. You have to have T cells attacking many different antigens to succeed because if you have a CAR-T cell that sees only one antigen, the tumor then has to mutate that antigen for escape the immune attack. If the therapy induces a new T-cell priming, this type of escape mechanism becomes much more difficult. "

Although most of the study was conducted in mice, the researchers showed that human cells coated with RCA antigens also stimulated human CAR-T cells, suggesting that the same approach might work in humans. human patients. The technology has been licensed to a company called Elicio Therapeutics, which seeks to test it with CAR-T cell therapies that are already under development.

"There is really no barrier to this treatment in patients very soon, because if we take a CAR-T lymphocyte and make it an arbitrary peptide ligand, we do not have to change the CAR-T lymphocytes," says Irvine. "I hope that, one way or another, this can be tested on patients one to two years from now."

The research was funded by the National Institutes of Health, the Marble Center for Nanomedicine Cancer, Johnson and Johnson, and the National Institute of General Medical Sciences.


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