Therapeutic cancer vaccines are designed to direct a person’s own immune cells against tumors. What if we could use that approach to prime CAR-T cells so that these engineered T cells—which are currently only able to tackle blood cancers—could work against solid tumors? Massachusetts Institute of Technology researchers did just that in mice.
Using a vaccine that super-charges CAR-Ts at the lymph nodes, an MIT team found that they could eliminate solid tumors in 60% of mice. After that, the animals also cleared re-injected tumor cells. The findings were published in Science.
CAR-T cell therapies use a patient’s own T Cells and a chimeric antigen receptor (CAR) to target cancer cells. Scientists believe one reason CAR-Ts don’t work well for solid tumors is that those cancers form a hostile environment around them that suppresses the T cells. The MIT team overcame this obstacle by stimulating CAR-T cells at the lymph nodes, the major sites of immune cells.
“Our hypothesis was that if you boosted those T cells through their CAR receptor in the lymph node, they would receive the right set of priming cues to make them more functional so they’d be resistant to shutdown and would still function when they got into the tumor,” Darrell Irvine, the study’s senior author, said in a statement.
Irvine’s team previously developed a method that delivers vaccines made of viral or bacterial antigens directly to lymph nodes, thereby provoking a stronger immune response. The vaccine is linked to a lipid tail that binds to albumin, a protein found in the bloodstream. Because albumin accumulates in lymph nodes, it allows the vaccine to hitchhike to the immune organ.
To build the new vaccine, the team used an antigen that stimulates the CAR-T cells. The antigen could be either the same tumor antigen to be targeted by the T cells, or a random molecule that the researchers selected.
The vaccines dramatically boosted CAR-T cell populations in mice, the researchers found. Mice given about 50,000 CAR-T cells sans vaccine showed nearly no CAR-T cells in the bloodstream. But CAR-T cells comprised up to 65% of the animals’ total T cell population in animals that got the vaccine.
The two-pronged eliminated such tumors as glioblastoma, breast and melanoma in 60% of mice, while solo CAR-T treatments produced no effect on those tumors, the team reported.
The animals that achieved tumor clearance were then re-challenged with tumor cells. Tumor cells that were identical to the original ones disappeared. Next, the researchers injected slightly different tumor cells, which did not express the antigen originally targeted by the CAR-T cells, and those tumor cells were eliminated, as well.
“That is another exciting aspect of this strategy,” Irvine said. “You need to have T cells attacking many different antigens to succeed, because if you have a CAR-T cell that sees only one antigen, then the tumor only has to mutate that one antigen to escape immune attack. If the therapy induces new T-cell priming, this kind of escape mechanism becomes much more difficult.”
Enthusiasm is swirling around the idea of using powerful CAR-T cells to treat solid tumors. Scientists at La Jolla Institute for Immunology found that removing a family of proteins called Nr4a transcription factors could rejuvenate CAR-T cells that have grown exhausted in the tumor microenvironment. Another team of scientists from MIT and Boston Children’s Hospital recently sought inspiration from alpacas and built CAR-T cells that can recognize certain proteins that protect tumors.
The MIT team’s technology has been licensed to Elicio Therapeutics, which raised $30 million to help fund its first human studies in the first half of 2020. “There’s really no barrier to doing this in patients pretty soon, because if we take a CAR-T cell and make an arbitrary peptide ligand for it, then we don't have to change the CAR-T cells,” Irvine said in the statement. “I'm hopeful that one way or another this can get tested in patients in the next one to two years.”