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Improving Immune System's Response To Cancer

For patients suffering from different forms of cancer like lymphoma, multiple myeloma, or certain types of leukemia, treatment using chimeric antigen receptor T cells or CAR T cells is sometimes the last hope for overcoming the cancer. The treatment involves taking T cells from the patient's blood and adding artificial receptors or the CARs to them in the lab.

As the guardians of our immune system, T cells are always on patrol in our blood vessels and tissues, where they hunt down foreign structures. Powered by CARs, T cells can also detect very specific surface structures on cancer cells. Once the CAR T cells are infused inside the patient, they circulate in the body like a living drug, which can attach itself to very specific tumor cells and destroy them.

The engineered immune cells remain in the body permanently and multiply. If the cancer flares up again, they'll go back into action. That is only in theory. However, in practice, many patients still get relapses. This is because the tumor cells can outwit the CAR T cells by producing more of the protein EBAG9 and by causing the T cells to produce more of it. In T cells, EBAG9 controls the release of cytotoxic enzymes, which affects the immune system response.

Recently, a team led by authors Armin Rehm and Uta Höpken from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association or MDC showed in the journal JCI Insight that shutting down the EBAG9 gene in mice led to a large increase in the immune response to cancer. The mice also developed more T memory cells. These cells are part of our immunological memory, which allows our immune system to respond better to a cancer antigen after encountering it previously.

As soon as the EBAG9 gene was discovered, researchers knew that it played an important role in cancer treatment. But it took a long time to identify what that role actually was. When the MDC team started working on it in 2009, they found that mice without the gene dealt with bacterial and viral infections much better than mice with the gene, and that they formed more T memory cells, which are of particular interest in tumor biology.

Then in 2015, lead author Anthea Wirges succeeded in curbing synthesis of the EBAG9 protein using microRNA. For the latest study, she used microRNA to cultivate "EBAG9-silenced" CAR T cells with different human leukemia or lymphoma cells. Just like in the mouse model, the silencing reduced tumor growth much more. Relapses also only developed much later.

"Releasing the EBAG9 brake allows the genetically engineered T cells to release more cytotoxic substances. However, they don't cause the strong cytokine storm that is typically a side effect of CAR therapy," says Wirges. In fact, the risk is minimized because fewer cells are used.

However, the first-line therapy for blood cancer will remain chemotherapy combined with conventional antibody therapy, as many patients respond very well to this. "CAR therapy only comes into play if the cancer returns. It's very expensive because it's an individual cellular product for a single person," says Höpken.

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