Immunotherapy is an effective method of cancer treatment by mobilizing the patient’s own immune system to kill tumor cells. Chimeric Antigen Receptor T cells (CAR-T) are T cells modified with a CAR gene, which has the ability to specifically recognize and clear tumor cells. Therefore, CAR-T cell therapy is considered as one of most promising tumor immunotherapies to cure cancer.
In order to develop precisely targeted, efficient, safe and high-quality CAR-T cells, CARsgen has conducted comprehensive studies in key technologies in CAR-T cell therapy, including drug target screening and validation, antibody screening and optimization, building next generation CAR-T technology platforms and manufacturing and production techniques. In other words, CARsgen has established an integrated R&D platform.
We have developed more than 10 distinct CAR-T candidate therapies to different targets and initiated 5 exploratory clinical studies in hematologic malignancies (2) and solid tumors (3).
Structure of chimeric antigen receptors:
Chimeric antigen receptors (CARs) are one kind of synthetic receptors that can change the specificity, function and metabolism of T cells. CARs usually contain a single-chain variable fragment (scFv), spacer, transmembrane domain, costimulatory domain and signal domain.
The scFv is a fusion protein that links the variable region of the heavy-chain with the variable region of the light-chain. The scFv specifically recognizes and binds the tumor-specific antigen, which is expressed on the surface of the cancer cell.
The spacer connects the scFv with the transmembrane domain, which affects the flexibility of the scFv.
The transmembrane domain passes through the cell membrane and anchors the CAR to the cell surface, which affects the expression of the CAR.
The costimulatory domain is the intracellular signal domain of T cell costimulatory proteins (such as CD28 and 4-1BB), which promote the activation, proliferation and cytokine secretion of the T cell.
The signal domain is the intracellular signal component of the T cell receptor (CD3 zeta), which mediates intracellular signal transduction pathways during T cell activation.
Anti-tumor mechanisms of CAR-T cells
After intravenous infusion, CAR-T cells travel to the tumor site where they recognize and kill tumor cells. The main anti-tumor immune activities of CAR-T cells are as follows:
1 Direct anti-tumor immune responses
CAR-T cells are activated and rapidly expand after specifically recognizing and binding tumor cells via the scFv. Cytotoxic T cells in CAR-T cells exert direct anti-tumor immune responses, including the release of perforin leading to the lysis of tumor cells and the secretion of granzyme to induce the apoptosis of tumor cells.
2 Indirect anti-tumor immune responses
On one hand, dead tumor cells release a large number of neoantigens that can be processed and presented by antigen-presenting cells (APCs). These APCs recruit and activate endogenous T cells to exert direct anti-tumor immune responses; on the other hand, the activation of helper T cells in CAR-T cells can release a large number of cytokines which promote the anti-tumor immune responses of various immune cell.