Significant Advances In The Treatment of Solid Tumors By CAR-T

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Significant Advances In The Treatment of Solid Tumors By CAR-T Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are receptor proteins that have been engineered to give T cells the new ability to target a specific protein. CAR-T, namely chimeric antigen receptor T cell immunotherapy. Simply speaking, 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 put these cells back into the patient to achieve the therapeutic effect of identifying and killing cancer cells.

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

Today, CAR-T has made many breakthroughs in hematological tumors. However, CAR-T has not made substantial breakthroughs in solid tumors till now.

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

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

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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 avoiding the manslaughter of normal cells with low expression of tumor antigens by CAR-T. 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 HER2 expression.

This research provides a solution for the application of CAR-T in solid tumors, which is a qualitative leap for CAR-T to conquer 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 (HER2) with low affinity. When fully activated, the synNotch receptor

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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 working.

Through this two-step recognition circuit, the target protein on the cell surface can be accurately distinguished, thereby controlling the function of CAR-T cells. Through this technology, CAR-T cells can only kill cancer cells in tumor tissues and won't 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 hurt normal cells.

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

The research team is very excited about the results. They are currently further developing the technology to apply it to the treatment of solid tumors such as ovarian cancer. With progresses of the research, the research team's goal is to develop CAR structures that target more antigens, and then combine this technology to apply to more solid tumors.

Cancer is one of the leading causes of death worldwide. With the advancement of science and technology, people have more methods to treat cancers. CAR-T is a type of immunotherapy. In addition to immunotherapy, surgical therapy, drug therapy, and gene therapy are also ways to treat cancer.

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Reference: T cell circuits that sense antigen density with an ultrasensitive threshold