For patients with lymphoma, multiple myeloma, or certain types of leukemia, chimeric antigen receptor T cell (CAR T cell) therapy is sometimes the last chance to beat the cancer. Treatment involves extracting T cells from a patient’s blood and adding an artificial receptor, a CAR, to them in the lab. As guardians of our immune system, T cells permanently patrol our blood vessels and tissues, where they search for foreign structures. CAR-equipped T cells can also detect very specific surface structures on cancer cells. Once the CAR T cells are returned to the patient by infusion, they circulate in the body as a living drug that can bind to and destroy very specific tumor cells.
The engineered immune cells stay in the body permanently and multiply. If the cancer comes back, they will get back into action. This is theory, at least. However, in practice, many patients still relapse. That’s because tumor cells can outcompete CAR T cells by making more of the protein EBAG9 — and by making the T cells make more of the protein, too. In T cells, EBAG9 inhibits the release of cytotoxic enzymes, thereby slowing the desired immune response.
A month ago, a team led by the last author of the Max Delbrück Center for Molecular Medicine of the Helmholtz Consortium (MDC) The journal JCI Insight, led by Dr. Armin Rehm and Dr. Uta Höpken, showed that switching off the EBAG9 gene in mice resulted in a consistently enhanced immune system response to cancer. The mice also developed more T memory cells. These cells are part of our immune memory, which enables our immune system to better respond to a cancer antigen after encountering it.
Now, the researchers have also demonstrated these key findings in human CAR T cells in vitro. This is a decisive step towards therapeutic use, the team wrote in Molecular Therapy
. “Turning off EBAG9 allows the body to eradicate tumor cells earlier and more completely. In addition to longer-lasting treatment success, this could create a real chance for cure,” Rehm said.
Release the brakes on immunotherapy
As soon as the EBAG9 gene was discovered, researchers recognized it plays an important role in cancer. But it took a long time to figure out what the character actually was. When the MDC team began their research in 2009, they found that mice without the gene were better able to cope with bacterial and viral infections than mice with the gene, and they formed more T memory cells, which is particularly important for tumor biology. interested.
Then in 2015, lead author Dr. Anthea Wirges successfully inhibited EBAG9 protein synthesis using microRNA. In the latest study, she used microRNA to grow “EBAG9-silenced” CAR T cells with different human leukemia or lymphoma cells. As in the mouse model, silencing reduced tumor growth even more. Relapse also only occurs much later.
“Release the EBAG9 brake allows genetically engineered T cells to release more cytotoxic substances. However, they do not cause strong Cytokine storm, which is often a side effect of CAR therapy,” Wirges said. In fact, the risk has been minimized as fewer units are used. “Closing the immune brakes works across the board. We can do this with every CAR T cell we produce — no matter what type of blood cancer it’s targeting.
The next step is clinical research
However, the first-line treatment for blood cancers will still be chemotherapy combined with conventional antibody therapy because many patients are The response was excellent. “CAR therapy only works when the cancer comes back. It’s very expensive because it’s a person’s personal cell product,” says Höpken. A single treatment with this product can save lives.
EBAG9’s work shows the importance of perseverance and patience to researchers. Wirges was motivated by the opportunity for real clinical application of her work. Rehm added: “Projects like this allow you to master techniques for basic research, Everything is then applied to translational research – right down to toxicology screening for regulatory processes. “Their project is now in its final stages: the researchers will be in November.
Thanks for their work from animal models and using Findings from in vitro experiments with human cells, the team now know that releasing the EBAG9 brake is highly effective and produces no more side effects than traditional CAR T erasure. “We now need bold clinicians and partners to fund clinical trials research,” Rehm said. If all goes well, therapy using EBAG9-silenced CAR T cells could be available to patients in as little as two years.
Anthea Wirges et al, EBAG9-silencing functions as an immune checkpoint without exacerbating adverse effects, Molecular Therapy
(2022). DOI: 10.1016/j.ymthe.2022.07.009
: Boosting the immune response to cancer (22 July 2022), Retrieved 2 September 2022 from https://medicalxpress.com/news/2022-07-immune-response-cancer.html
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