Utilizing Immune-Oncology to Attack Tumors

In 2017, the first immuno-oncology cell therapies, known as chimeric antigen receptor T cells, or CAR T, were approved by the U.S. Food and Drug Administration. Immuno-oncology cell therapy is a field that leverages the immune system by modifying and thereby enhancing, immune cells to target cancer. It accomplishes this by interdicting pathways that maintain checks and balances on cellular elements of the immune system, thereby disrupting the tolerance of the body to the growth and spread of cancer.

CAR-T therapies have had unprecedented success in blood cancers, such as certain leukemias and lymphomas. They have shown high response rates and redefined the treatment of patients who have exhausted other options. The therapeutic success relies on an antibody fragment that binds to a surface protein on leukemias and lymphomas; the protein is known as CD19. The antibody fragment is linked to stimulatory and signaling molecules that fire upon binding of the antibody with the CD19 molecule, thereby activating the T cells and making them destroy the cancer cell.

CAR T therapies have shown limited success in solid tumors since they do not typically express a molecule on their surface that is unique to the solid tumor and not to normal tissue. This, coupled with the complex matrix in which cancer cells grow, makes it challenging to develop cellular therapies for solid tumors.

One way to overcome this challenge is to target proteins expressed inside the cell rather than large cell surface proteins. This sort of immune response involves the activation of T cells against a portion of an internal protein that the T cell sees as foreign. These protein fragments, known as peptides, dock with protein structures known as major histocompatibility antigens (MHC) on the cell surface, which is the cellular network that governs the presentation of self versus non-self peptides and lets T cells distinguish friend from foe.

T cells are some of the “surveyors and assassins” of the immune system. They have T-cell receptors (TCR) on their surface, and they circulate through the body, binding foreign peptides on the surface of cells that are infected by foreign organisms such as viruses and bacteria. When a cell is infected, bits of that organism’s protein makes it to the surface, docking with the right MHC. Surveying T cells can see these proteins through their TCRs and kill them to prevent propagation of the infection.