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Cart cells in solid tumors

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A promising new approach to treating some types of cancer is to program the patient’s own T cells so that they can destroy the cancer cells. This approach, called CAR-T cell therapy, is currently available against certain types of leukemia, but so far it does not treat solid tumors such as lung or breast tumors well.

Now, in a new study, researchers from the Massachusetts Institute of Technology have developed a new approach to improve this therapy, making it a weapon against almost any type of cancer. Specifically, they developed a vaccine that significantly enhanced the anti-tumor T cell population and allowed these T cells to aggressively invade solid tumors. The results of the study were published in the July 12, 2019 issue of Science, titled “Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor.”

In a study of mice, these researchers found that they were able to completely eliminate 60% of the solid tumors in mice that received CAR-T cell therapy but also received booster vaccination. In treating solid tumors, these genetically modified T cells alone have little effect.

Darrell Irvine, author of the paper and deputy director of the Koch Institute for Comprehensive Cancer Research at the Massachusetts Institute of Technology, said, “By adding a vaccine, CAR-T cell therapy, which had no effect on survival, resulted in complete remission in more than half of the mice treated with the vaccine.” In addition, the first author of the paper was Leyuan Ma, a postdoctoral fellow at the Massachusetts Institute of Technology.

Targeting tumors

So far, the FDA has approved two types of CAR-T cell therapy, and both of them are used to treat leukemia. In both therapies, T cells extracted from the patient’s blood are programmed to target proteins or antigens found on the surface of B cells. (“CAR” in CAR-T cell therapy is an abbreviation for chimeric antigen receptor.)

Scientists believe that one reason such therapies do not work well for solid tumors is that tumors often create an immunosuppressive environment that loses function before T cells reach their targets. To solve this problem, given that lymph nodes have a large population of immune cells, Irvine and his team decided to try to provide a vaccine that enters lymph nodes in order to stimulate CAR-T cells there.

“Our guess is that if these T cells can be boosted through the CAR receptor in the lymph nodes, they will receive the correct set of priming signals to make them more functional, so that they can resist shutdown and still function when they enter the tumor,” said Irvine.

To develop such a vaccine, the Irvine team used techniques they had discovered several years earlier. They found that by linking the vaccine together with fat molecules called lipid tails, they were able to deliver this vaccine more effectively into the lymph nodes. This lipid tail binds to a protein found in the blood called albumin, which allows the vaccine to hitchhike directly to the lymph nodes.

In addition to this lipid tail, this vaccine contains an antigen that stimulates CAR-T cells once they reach the lymph nodes. This antigen can be the same tumor antigen targeted by these T cells or an arbitrary molecule of choice for these researchers. For the latter case, CAR-T cells must be re-engineered so that they can be activated by both this tumor antigen and this arbitrary molecule.

When tested in mice, these researchers found that either type of vaccine significantly boosted T cell responses. When mice were given approximately 50,000 CAR-T cells but were not vaccinated, CAR-T cells were barely detectable in their bloodstream. In contrast, when the booster vaccine was given the day after the T cell infusion and again one week later, CAR-T cells proliferated until they constituted 65% of the total T cell population in these mice after two weeks of treatment.

This dramatic enhancement of the CAR-T cell population results in complete clearance of glioblastoma, mammary adenoma, and melanoma in many mice. In the absence of vaccination, CAR-T cells had no effect on tumors, whereas after vaccination, CAR-T cells cleared tumors in 60% of mice.

Long-term memory

Irvine said the technique is also expected to prevent tumor recurrence. Approximately 75 days after the initial treatment, these researchers injected these mice with the same tumor cells as the cells that formed the original tumor, and they were subsequently cleared by the immune system. Then about 50 days later, they injected slightly different tumor cells that did not express the antigen targeted by naïve CAR-T cells, and these mice were also able to eliminate these tumor cells.

This suggests that once these CAR-T cells begin to destroy the tumor, the immune system is able to detect other tumor antigens and generate a “memory” T cell population that also targets these tumor antigens.

“If we select mice that appear to be cured and rechallenge them with tumor cells, then they will completely eliminate these tumor cells. This is another exciting aspect of such a strategy. One needs to let T cells attack many different antigens to succeed, because if CAR-T cells recognize only one antigen, then the tumor only needs to let this antigen mutate to escape the immune attack. If this therapy induces new T cell priming, then this escape mechanism will become more difficult.” Irvine added.

Although most of this study was performed in mice, these researchers found that human cells coated with CAR antigens also stimulate human CAR-T cells, suggesting that this same approach may also work in human patients. This technology has been licensed to a company called Elicio Therapeutics, which is seeking to test it using CAR-T cell therapies already in development.

Irvine said, “There is really no barrier to doing this quickly in patients, because if we take CAR-T cells and equip them with an arbitrary peptide ligand, then we don’t have to change these CAR-T cells. I hope that within the next one to two years, this method can be tested on patients anyway.”

About the author

Starting from a small supplier of proteins and enzymes for academic institutes and biotech companies, Creative BioMart has always been focusing on developing high quality protein products including recombinant protein, GMP proteins, native proteins, assay kit, etc. and efficient protein service. Over the past decade, our products and services are proved to have served our customers well and our brand has become one of the most trustworthy in the market.

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