Engineering CAR T Cells: Design Concepts
Chimeric antigen receptor (CAR) T cell therapy is a promising new treatment for cancer. CAR T cells are engineered to express a chimeric antigen receptor that recognizes a specific antigen on the surface of cancer cells. When CAR T cells bind to the antigen, they are activated and kill the cancer cells.
The design of CAR T cells is critical to their safety and efficacy. There are several different design concepts that can be used to engineer CAR T cells. The choice of design concept depends on the specific cancer being targeted and the desired therapeutic effect.
Single-Chain Variable Fragment (scFv) CARs
scFv CARs are the most common type of CAR T cell. They are composed of a single-chain variable fragment (scFv) of an antibody that recognizes the target antigen. The scFv is fused to the cytoplasmic domain of a T cell receptor (TCR) signaling molecule. When the scFv binds to the antigen, it triggers the TCR signaling pathway, which leads to the activation of the CAR T cell.
scFv CARs are relatively easy to design and manufacture. However, they can be less specific than other types of CAR T cells, and they may have a higher risk of off-target effects.
Tandem CARs
Tandem CARs are composed of two scFvs that recognize different epitopes on the target antigen. The two scFvs are fused to the cytoplasmic domains of different TCR signaling molecules. When both scFvs bind to the antigen, they trigger the TCR signaling pathway and activate the CAR T cell.
Tandem CARs are more specific than scFv CARs, and they have a lower risk of off-target effects. However, they are also more complex to design and manufacture.
Switch CARs
Switch CARs are composed of an scFv that recognizes the target antigen and a switch domain that is fused to the cytoplasmic domain of a TCR signaling molecule. When the scFv binds to the antigen, it triggers a conformational change in the switch domain that activates the TCR signaling pathway and activates the CAR T cell.
Switch CARs are more specific than scFv CARs, and they have a lower risk of off-target effects. However, they are also more complex to design and manufacture.
Co-Stimulatory CARs
Co-stimulatory CARs are composed of an scFv that recognizes the target antigen and a co-stimulatory domain that is fused to the cytoplasmic domain of a TCR signaling molecule. When the scFv binds to the antigen, it triggers the TCR signaling pathway and the co-stimulatory domain provides an additional signal that enhances the activation of the CAR T cell.
Co-stimulatory CARs are more potent than scFv CARs, and they have a lower risk of exhaustion. However, they are also more complex to design and manufacture.
The Future of CAR T Cell Design
The field of CAR T cell therapy is rapidly evolving. New design concepts are being developed all the time. These new concepts are aimed at improving the safety, efficacy, and specificity of CAR T cells.
Some of the most promising new design concepts include:
- Universal CARs: Universal CARs are designed to recognize a wide range of cancer antigens. This would make them more versatile and easier to use in the treatment of different types of cancer.
- Multiplex CARs: Multiplex CARs are designed to recognize multiple different antigens. This would allow them to target cancer cells that have multiple different mutations.
- Inducible CARs: Inducible CARs are designed to be activated only in the presence of a specific signal. This would allow them to be turned on and off as needed, which would reduce the risk of side effects.
These new design concepts are still in the early stages of development. However, they have the potential to revolutionize the field of CAR T cell therapy.
