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.

  • Single-chain
    Variable
    Fragment (scFv)

    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.

  • Spacer

    The spacer connects the scFv with the transmembrane domain, which affects the flexibility of the scFv.

  • Transmembrane
    Domain

    The transmembrane domain passes through the cell membrane and anchors the CAR to the cell surface, which affects the expression of the CAR.

  • Costimulatory
    Domain

    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.

  • Signal Domain

    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.

Therapeutic process of CAR-T cells