2. Sept. 2021

Press release;

Veronika Mancikova, Michal Smida and their colleagues from the Functional Genomics Research group based at CEITEC MU, in collaboration with the Department of Internal Medicine – Hematology and Oncology of the University Hospital Brno, have discovered a new previously unknown epigenetic mechanism, that is responsible for the downregulation of the CD19 antigen – a crucial antigen for the effective binding of genetically engineered CAR-T cells that are used to fight cancer when other conventional treatment methods fail. This discovery could enhance the response rate of this extremely expensive personalized cancer treatment. The research findings were published in the Journal for Immunotherapy of Cancer (IF 13.75).

Cancer immunotherapy with a patient´s own genetically engineered T lymphocytes (named CAR-T cells) represents a novel and promising way of curing patients particularly with haematological malignancies. While its efficiency in solid cancers is so far rather limited, its application in hemato-oncology has reached a remarkable success rate, especially with CAR-T cells targeting CD19 protein present on B lymphocytes.

Therapy with CAR-T cells has sparked high hopes of finally curing some hemato-oncological patients unresponsive to standard treatment options. It has triggered enormous interest worldwide and is being successfully applied also in the Czech Republic. The procedure of generating CAR-T cells is however technically and financially very demanding. The costs of CAR-T cell therapy for one patient reaches 10 million Czech crowns. However, 30–60% of patients eventually suffer from relapse, which is often caused by CD19 target protein disappearance from the surface of malignant cells. While some mechanisms of CD19 loss were previously known, a large fraction of cases remain unexplained. Furthermore, none of the currently known mechanisms responsible for the CD19 disappearance could so far be used to prevent or revert the relapse. A team of Czech scientists, led by Michal Smida, have discovered a new mechanism causing the loss of CD19 antigen and they have described how the levels of CD19 can be regulated.

“We have shown for the first time that CD19 is regulated through an epigenetic mechanism, which allows for plasticity and active fine-tuning of CD19 levels by the malignant cells. Moreover, we could also demonstrate that by inhibiting this epigenetic mechanism, we can revert the defect and enhance CD19 expression levels again,” explains Michal Smida. “This is also the first discovered mechanism that can be pharmacologically exploited. We can finally control the CD19 levels by the use of a specific drug treatment. Our findings propose the use of DNA demethylating agents to block the described epigenetic mechanism and thereby hopefully avoid the failure of CAR-T cells. Once this is successfully tested in various mouse models, these agents could be used in combination with CAR-T cell therapy to enhance its response rate,” concludes Michal Smida.

The path to the discovery…

The research team has established an in vivo mouse model, where they first generated B-cell chronic lymphocytic leukemia (CLL) and then they treated these mice with their in-house produced CAR-T cells. Once these mice relapsed, scientists isolated relapsed leukemic cells and analysed them in the laboratory for changes in CD19 expression and CD19 gene promotor methylation. The scientists reproduced their findings in multiple in vitro experiments using different cell lines as well as primary CLL samples. Potential use of DNA demethylating agents for enhancing CD19 expression levels was finally demonstrated in the mouse model again.

This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie actions and it is co-financed by the South Moravian Region under grant agreement No. 665860. It also has been financed by a grant MUNI/A/1595/2020 and Martina Roeselová Memorial Foundation.

What is CAR-T cell therapy and how does it work?

Our immune system works by keeping track of all the substances normally found in your body. Any new substance the immune system doesn't recognize raises an alarm, causing the immune system to attack it. Chimeric antigen receptor (CAR) T-cell therapy is a way to get immune cells called T cells (a type of white blood cell) to fight cancer by changing them in the lab so they can find and destroy cancer cells. CAR T-cell therapy is also sometimes talked about as a type of cell-based gene therapy, because it involves altering the genes inside T cells to help them attack the cancer. This type of treatment can be very helpful in treating some types of cancer, even when other treatments are no longer working.

The immune system recognizes foreign substances in the body by finding proteins called antigens on the surface of those cells. Immune cells called T cells have their own proteins called receptors that attach to foreign antigens and help trigger other parts of the immune system to destroy the foreign substance. The relationship between antigens and immune receptors is like a lock and key. Just as a lock can only be opened with the right key, each foreign antigen has a unique immune receptor that is able to bind to it. Cancer cells also have antigens, but if your immune cells don't have the right receptors, they can't attach to the antigens and help destroy the cancer cells.

In CAR T-cell therapies, T cells are taken from the patient's blood and are changed in the lab by adding a gene for a man-made receptor (called a chimeric antigen receptor or CAR). This helps them better identify specific cancer cell antigens. The CAR T cells are then given back to the patient. Since different cancers have different antigens, each CAR is made for a specific cancer's antigen. For example, in certain kinds of leukemia or lymphoma, the cancer cells have an antigen called CD19. The CAR T-cell therapies to treat these cancers are made to attach to the CD19 antigen and will not work for a cancer that does not have the CD19 antigen.

To produce CAR T cells, white blood cells (which include T cells) are first removed from the patient’s blood using a procedure called leukapheresis. After the white cells are removed, the T cells are separated, sent to the lab, and altered by adding the gene for the specific chimeric antigen receptor (CAR). This makes them CAR T cells. These cells are then grown and multiplied in the lab. It can take several weeks to make the large number of CAR T cells needed for this therapy. Once enough CAR T cells have been made, they will be given back to the patient. Once the CAR T cells start binding with cancer cells, they start to increase in number and can help destroy even more cancer cells.

Source: Cancer.org


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