Chimeric antigen receptor

Chimeric Antigen Receptors (CARs) are engineered receptors that graft an arbitrary specificity onto an immune effector cell. They are a prominent form of immunotherapy used primarily in the treatment of cancer. CARs are most commonly expressed on the surface of T cells, creating what is known as CAR T-cells.

Structure and Function

CARs are composed of several key components:

• Antigen Recognition Domain: This is typically a single-chain variable fragment (scFv) derived from a monoclonal antibody. It is responsible for recognizing and binding to a specific antigen on the surface of target cells.

• Hinge Region: This flexible region connects the antigen recognition domain to the transmembrane domain, allowing for optimal positioning and movement.

• Transmembrane Domain: This anchors the CAR to the T-cell membrane.

• Intracellular Signaling Domains: These include the CD3ζ chain and one or more co-stimulatory domains (such as CD28 or 4-1BB) that activate the T-cell upon antigen binding.

Generations of CARs

CARs have evolved through several generations, each with improvements in design and function:

• First Generation: These CARs contain only the CD3ζ signaling domain. They showed limited efficacy due to insufficient T-cell activation and persistence.

• Second Generation: These include an additional co-stimulatory domain (e.g., CD28 or 4-1BB), enhancing T-cell activation and persistence.

• Third Generation: These incorporate two co-stimulatory domains, further improving T-cell function.

• Fourth Generation: Also known as TRUCKs (T-cells Redirected for Universal Cytokine Killing), these CARs are designed to secrete cytokines upon activation, enhancing the immune response.

Applications in Cancer Therapy

CAR T-cell therapy has shown remarkable success in treating certain types of hematological malignancies, such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma. The therapy involves:

1. Collecting T-cells from the patient. 2. Genetically engineering these T-cells to express CARs. 3. Expanding the modified T-cells in vitro. 4. Infusing the CAR T-cells back into the patient.

Challenges and Limitations

Despite its success, CAR T-cell therapy faces several challenges:

• Cytokine Release Syndrome (CRS): A potentially severe side effect caused by the rapid release of cytokines from activated T-cells.

• Neurotoxicity: Some patients experience neurological side effects, the mechanisms of which are not fully understood.

• Antigen Escape: Tumor cells may lose or downregulate the target antigen, leading to treatment resistance.

• Solid Tumors: CAR T-cell therapy has been less effective against solid tumors due to the immunosuppressive tumor microenvironment and lack of specific antigens.

Future Directions

Research is ongoing to improve CAR T-cell therapy, including:

• Developing CARs targeting multiple antigens to prevent escape.
• Engineering "off-the-shelf" CAR T-cells from allogeneic donors.
• Enhancing T-cell trafficking and persistence in solid tumors.

See Also

• Immunotherapy
• Monoclonal antibody
• T cell

References

• June, C. H., et al. (2018). "CAR T cell immunotherapy for human cancer." Science, 359(6382), 1361-1365.
• Maude, S. L., et al. (2014). "Chimeric antigen receptor T cells for sustained remissions in leukemia." New England Journal of Medicine, 371(16), 1507-1517.