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

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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