December 8, 2021

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CAR-T treats solid tumors: Only killing cancer cells

CAR-T treats solid tumors: Only killing cancer cells

 

CAR-T treats solid tumors: Only killing cancer cells and not healthy cells. Through this technology, CAR-T cells can only kill cancer cells in tumor tissues, but not normal cells with low expression of HER2.

CAR-T treats solid tumors: Only killing cancer cells


CAR-T, namely chimeric antigen receptor T cell immunotherapy. To put it simply, CAR-T is to transform the patient’s immune T cells in vitro through biotechnology to make them recognize the antigens on the surface of tumor cells, and then inject these cells back into the patient to achieve the therapeutic effect of identifying and killing cancer cells.


In 2017, the FDA approved CAR-T therapy for the first time for the treatment of blood cancers such as leukemia and lymphoma. The successful application of CAR-T therapy has rekindled hope for many desperate people who are waiting for bone marrow matching. It also marks the arrival of the era of cell therapy.

Today, CAR-T has become one of the most important new developments in cancer immunotherapy, and many breakthroughs have been made in hematological tumors. However, so far, CAR-T has not achieved substantial results in solid tumors. breakthrough.

In many cancer types, there are a large number of specific proteins on the surface of cancer cells, but because this protein is often also present in a small amount in normal tissues, this causes CAR-T cells to be unable to distinguish cancer cells from normal cells, resulting in Normal cells and organs are attacked, leading to fatal adverse reactions related to treatment.

On March 11, 2021, researchers from the University of California, San Francisco published a research paper titled “T cell circuits that sense antigen density with an ultrasensitive threshold” in the top international academic journal Science.

The study designed a two-step positive feedback circuit that allows killer T cells to distinguish targets based on the S-type antigen density threshold, thereby solving the manslaughter of normal cells with low expression of tumor antigens by CAR-T cell therapy. In HER2 expressing cancer cells and mouse tumor models, this method can accurately and effectively kill cancer cells with high HER2 expression, but not normal cells with low expression of HER2.

This research has found a solution to apply CAR-T cell therapy to solid tumors, which is a qualitative leap for CAR-T cell therapy to overcome solid tumors.

 

HER2 (Human Epidermal Growth Factor Receptor-2) is a protein marker for breast cancer, ovarian cancer, and stomach cancer and other abdominal tumors. Due to gene amplification, the expression of HER2 doubles in tumors, so the protein is abundantly present on the surface of tumor cells.

Ideal therapeutic T cells can distinguish tumor cells expressing high antigen density from normal cells expressing low antigen levels. To achieve this, T cells need to have an S-shaped hypersensitivity dose-response curve.


The research team designed a two-step recognition circuit. The synNotch receptor detects the antigen with low affinity (HER2). When fully activated, the synNotch receptor induces the expression of high-affinity CAR. The low-affinity synNotch acts as a high-antigen density filter, and the high-affinity CAR activates the killing and proliferation of T cells, acting as an amplifier.

Through this T cell design with ultra-sensitive antigen density sensing, the low-affinity synNotch receptor acts as a filter. Only when it encounters tumor cells that express HER2, CAR-T cells will activate and kill tumor cells. When encountering normal cells with low expression of HER2, CAR-T cells will not start.

CAR-T treats solid tumors: Only killing cancer cells

Through this two-step identification circuit, the target protein on the cell surface is distinguished precisely by machine, thereby controlling the function of CAR-T cells. Through this technology, CAR-T cells can only kill cancer cells in tumor tissues. It will not kill normal cells with low expression of HER2.

Next, the research team conducted verification at the in vitro cell level and mouse solid tumor models. The experimental results showed that the method can kill cancer cells accurately and effectively, but not normal cells.

CAR-T treats solid tumors: Only killing cancer cells


Although CAR-T can truly conquer solid tumors, several other challenges need to be overcome, including tumor heterogeneity, suppressive tumor microenvironment, and improving the transport of T cells to tumors. However, this research achieves ultra-sensitive tumor antigens. The ability of density discrimination provides a key tool for expanding the scope of CAR-T treatment for solid tumors.

For these experimental results, the research team is very excited. The research team is currently further developing the technology to apply it to the treatment of solid tumors such as ovarian cancer. As the research progresses, the goal of the research team is to develop CAR structures that target more antigens, and then combine this technology to apply to more solid tumors. This is like a “multi-warhead missile”, cancer cells will be difficult to resist.

 

 

 

 

(source:internet, reference only)


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