1. What is Cellular Immunotherapy?

In layman's terms, cellular immunotherapy is an emerging technology that uses self-cells to express and modify, and can directly activate a series of effector cells in the body to help the body kill or kill cancerous cells. It is divided into Car-T, Car-NK and TCR.

CAR-T technology (Chimeric Antigen Receptor T-Cell Immunotherapy), also known as chimeric antigen receptor T cell technology, is a new cancer immunotherapy strategy used to produce T cells with specific response to cancer cells, which can greatly enhance the ability of T cells to attack tumor cells. CAR-T cells are composed of three main parts: external antigen recognition structure, internal signal transduction module and negative regulation module. External antigen recognition structure: that is, positive signal complex (PCS), which is composed of single-chain antibodies and can selectively bind to the antigen surface on tumor cells; Internal signal transduction module: composed of CD3ζ chain and 1-2 co-stimulatory molecules (such as CD28 or 4-1BB), which can transmit stimulation signals; Negative regulation module: such as CD28 inner handle, can negatively regulate the activation degree of CAR-T cells. The above three parts form a complete CAR-T cell.

T cells, also known as T lymphocytes, are a type of white blood cell in the human body. They are derived from bone marrow hematopoietic stem cells, mature in the thymus, and then transported to the blood, lymph and other tissues and organs to play the role of the immune system. CAR-T technology uses genetic engineering technology to modify the receptor genes on the surface of T cells so that the surface of T cells express a protein called chimeric antigen receptor (CAR). There is a specific antigen binding region in the CAR cell that can identify specific antigens on the surface of cancer cells. Once bound to these cancer cells, the CAR-T cell will be activated and release a large amount of cytotoxins to kill cancer cells.

CAR-T structure

2. Development of CAR-T Technology:

The core structure of the first-generation CAR-T cells is a complex ITAM region, which contains the ζ chain of the CD3 molecule, and its internal cell structure is also very simple. However, it cannot produce costimulatory signals and has not achieved the expected results in clinical applications.

The second-generation CAR-T cells added costimulatory molecules from CD28 or CD137 (4-1BB) to the ITAM region, which greatly improved the activation ability of CAR-T cells and showed amazing efficacy in clinical treatment. However, the reverse transcription transfection virus vector used by the second-generation CAR-T cells has limited gene fragments to accommodate and carry, and it is not easy to transfect the two costimulatory signal molecules of the ITAM region of CD28 and CD137 into T lymphocytes at the same time.

The main structure of the third-generation CAR-T cells is roughly the same as that of the second generation. Although the third-generation CAR-T cells use lentiviruses that can carry larger gene fragments into T lymphocytes as transfection vectors and can contain 2 or more costimulatory signal ITAM regions, some studies have shown that the killing activity of the third-generation CAR-T cells has not been significantly improved.

The fourth-generation CAR-T cells are a new type of CAR-T cells that solves safety issues such as precise treatment of tumor cells and prevention of recurrence during CAR-T cell therapy and enhances its killing effect in tumor tissues, also known as precision CAR-T cells. Among them, adding suicide genes or controllable suicide genes is a feasible solution, but it needs further research and optimization. At the same time, improving the infiltration of CAR-T cells in tumor tissues by adding receptor structures of cytokines or chemokines is also one of the common design strategies for the fourth-generation CAR-T cells. Although the current application of CAR-T cells is still subject to certain limitations, it is believed that with the continuous advancement of technology, its potential in the precise treatment of tumors and other diseases will be greater.

At present, after years of technical accumulation, TechBio has built a complete phage display technology system and yeast display system to provide customers with high-quality CAR lead antibody molecule discovery services.

development history of CAR-T cells

3. Application of CAR-T Technology:

CAR-T therapy refers to chimeric antigen receptor T cell immunotherapy, which is a new type of precision targeted therapy for treating tumors. The principle of CAR-T technology: assess whether it meets the indications for CAR-T treatment - collect peripheral blood and separate T cells - convert T cells into CAR-T cells - expand CAR-T cells - return CAR-T cells to the human body - monitor the response. These CAR-T cells will find and kill cancer cells and continue to be active for months to years, thus providing long-term therapeutic effects.

At present, most CAR-T therapies are still in the clinical trial stage, and the treatment scope is concentrated in the following areas:

1. Relapsed acute B-lineage lymphoblastic leukemia (recurrence after treatment relief) or refractory acute B-lineage lymphoblastic leukemia (the condition has not been relieved after using other anti-leukemia treatments).

2. Large B-cell non-Hodgkin's lymphoma that has failed to be treated with two or more methods.

3. CD19-positive relapsed and refractory malignant lymphoma.

4. Acute lymphoblastic leukemia with CD22 positive after CD19 treatment failure.

CAR-T therapy has also been studied in clinical trials in other anti-tumor fields, but the effect is still unclear.

4. Prospects and Challenges of CAR-T Technology:

CAR-T cells have been widely used in cell immunotherapy for various tumors. According to statistics, there are currently more than 300 CAR-T cell therapy clinical trial projects approved by drug regulatory authorities in many countries, including the US FDA, and some CAR-T cells have been put on the market. Although the effect of each clinical project varies due to the different sources and preparation processes of CAR-T cells, pretreatment and combination drugs, it generally shows that CAR-T cells are effective in treating tumors, with an effective rate between 30% and 70%, and even up to 90%. For example, Novartis CTL019, approved by the US FDA, has a complete remission rate of 93% in the treatment of non-Hodgkin's lymphoma.

Tek Biotech has completed more than 270 different antibody discovery projects for customers from all over the world. 90% of them are alpaca nano-antibody development and verification services.

With the continuous deepening of tumor immunology research, tumor immunotherapy has made significant progress. New immunotherapy methods have entered the clinic one after another, among which CAR-T cell therapy has become a tumor cell immunotherapy that has attracted much attention and has made great progress in the treatment of hematological malignancies such as leukemia.