Molecule of the Month: Chimeric Antigen Receptors

The immune system is expert at defending us from dangers, but when faced with cancer cells, the immune system often fails. Cancer cells are normal human cells that have been transformed into rogues. They usually have many genetic changes that allow them to grow without normal limitations. Unfortunately, most of these genetic changes mutate proteins that are inside the cancer cell, so the immune system may not detect them. Today, researchers are developing ways to retool the immune system to fight specific forms of cancer.

T cells have the ability to recognize virus-infected cells using T-cell receptors, and then destroy them. Unfortunately T cells are not as effective against cancer cells, because the molecules on the surface of cancer cells often look much like the molecules on normal cells. Chimeric antigen receptors (CAR) are a way for doctors to arm T cells with the ability to recognize cancer cells. Researchers remove T cells from a cancer patient and add a gene for a CAR that recognizes their form of cancer. When these “CART” cells are returned to the patient, they search for cancer cells and destroy them.

Chimeric antigen receptors are built by connecting several functional parts from different proteins, each with a specific job. A single-chain antibody variable fragment (Fv) recognizes a known cancer cell protein, targeting the tumor. These are generally engineered from monoclonal antibodies by using only the domains at the tip of the antibody, and connecting the two chains with a flexible linker. The antibody portion is connected to a transmembrane segment with another flexible linker. Inside the cell, one or more domains are taken from signaling proteins, which will activate the T cell once it finds a tumor cell.

The CART therapy tisagenlecleucel was recently approved by the US FDA for treatment of a form of leukemia that is particularly common in children. In this leukemia, known as acute lymphoblastic leukemia (ALL), normal B cells are transformed into cancer cells that fail to develop correctly. The CART therapy targets CD19, a protein normally found of the surface of B cells, and also found on the surface of these transformed leukemia cells. The chimeric antigen receptor is a bit more advanced than the model shown above, composed of pieces from four molecules: a single-chain antibody, a flexible linker and transmembrane section from CD8 alpha, and two signaling domains from CD3 zeta and 4-1BB (CD137). The engineered T cells are remarkably effective for this particular form of cancer, leading to remission for most of the patients.