Therapeutic cancer vaccines are designed to direct the immune cells against tumors. What if we could use this approach to start T-CAR cells so that these modified T cells, which are currently only able to fight against blood cancers, could act against solid tumors? Researchers at the Massachusetts Institute of Technology did just that in the mouse.
Using a CAR-T overload vaccine at the lymph node level, an MIT team found that it could eliminate solid tumors in 60% of mice. After that, the animals also removed the reinjected tumor cells. The results were published in Science.
CAR-T cell therapies use patient T cells and a chimeric antigen receptor (CAR) to target cancer cells. Scientists believe that one of the reasons why T – CARs do not work well for solid tumors is that these cancers form a hostile environment around them, which suppresses T – cells. MIT team overcame this hurdle by stimulating CAR-T cells at the lymph nodes, major sites of immune 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 continue to function as soon as they enter the system. the tumor, "said Darrell Irvine, lead author of the study, in a statement.
The Irvine team has previously developed a method to deliver vaccines containing viral or bacterial antigens directly to the lymph nodes, resulting in a stronger immune response. The vaccine is linked to a lipid tail that binds to albumin, a protein found in the blood. Because albumin accumulates in the lymph nodes, it allows the vaccine to hitchhike up to the body's immune system.
To build the new vaccine, the team used an antigen stimulating CAR-T cells. The antigen could be either the same tumor antigen targeted by T cells, or a random molecule chosen by the researchers.
The researchers found that vaccines dramatically increased CAR-T cell populations in mice. Mice that received about 50,000 vaccine-free CAR-T cells showed virtually no T-Cells in the blood. However, CAR-T cells accounted for up to 65% of the total T cell population in vaccinated animals.
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Both types of tumors eliminated tumors such as glioblastoma, breast and melanoma in 60% of mice, while solitary CAR-T treatments had no effect on these tumors, the team reported.
Animals having reached the clearance of the tumor were then challenged with tumor cells. Tumor cells identical to those of origin have disappeared. Then the researchers injected slightly different tumor cells, which did not express the antigen initially targeted by T-CAR cells, and these tumor cells were also eliminated.
"This is another exciting part of this strategy," said Irvine. "To be successful, T cells must attack many different antigens, because if you have a T-cell that detects only one antigen, then it is enough for the tumor to mutate that antigen to escape it." immune attack. If the therapy induces a new T-cell priming, this type of escape mechanism becomes much more difficult. "
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The enthusiasm revolves around the idea of using powerful CAR-T cells to treat solid tumors. Scientists at the La Jolla Institute of Immunology have discovered that removing a family of proteins called Nr4a transcription factors could rejuvenate the CAR-T cells that have depleted in the tumor microenvironment. Another team of scientists from MIT and the Boston Children's Hospital recently relied on alpacas and constructed CAR-T cells that recognize certain tumor-protecting proteins.
The technology of the MIT team was licensed to Elicio Therapeutics, which raised $ 30 million to fund its first human studies in the first half of 2020. "There really does not prevent patients from doing it soon because if we take a CAR-T cell treatment and make an arbitrary peptide ligand for that, then we do not have to change the cells CAR- T, "said Irvine in the statement." I hope that in one way or another, this will be tested on patients one to two years from now. "