For many years, cancer has been treated with surgery, radiation, chemotherapy, and subsequently with synthetic and biologic agents that target specific molecules in tumor cells. Most recently, treatment of many cancers has been advanced by novel molecules (e.g., ipilimumab, pembrolizumab, nivolumab) that augment the body‘s ability to detect and destroy cancer cells. However, malignant cells can escape the selective pressure of the immune system by acquiring immunoediting changes that allow them to evade and proliferate. Immunoselection leads to the survival of only those malignant cells that can evade detection and destruction by the immune system (immunoescape), leading to unregulated proliferation. One of the newest approaches to treating cancers is focused on overcoming these pathways to survival and proliferation of tumor cells.
Now, more highly targeted cell-based therapies have been developed and shown to be effective for destroying tumor cells resistant to other cancer treatments. This new approach employs chimeric antigen receptor (CAR) T-cells. These are reprogrammed T-cells that selectively target and destroy tumor cells. The therapy involves collecting T-cells from a cancer patient and then modifying them by adding genes that code for elements that target and facilitate killing of that patient‘s tumor cells. The genes added encode the CAR, which consists of a targeting element, often derived from a monoclonal antibody, a transmembrane domain, a co-stimulatory domain that is important for sustained activity of CAR-T cells, and CD3ζ, a T cell surface glycoprotein that plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways that is important for tumor cell killing. These customized T-cells are then infused back into the patient to seek and destroy tumor cells.
While CAR-T cells are being developed for a large number of targets, the one for which we have the most clinical information is CD19. It has been a major focus of attention because it is an ideal target for CAR-T cells in certain hematological malignancies. CD19 is a cell surface protein whose expression is restricted to B cells and B cell precursors. It is not present on hematopoietic stem cells, but is expressed by most B-cell malignancies, including B-cell acute lymphoblastic leukemia and diffuse large B cell lymphoma. Clinical trial results in patients with acute lymphoblastic leukemia and diffuse large B cell lymphoma resistant to other therapies have demonstrated remarkable efficacy for CAR-T cell therapy targeting CD19. The success of early trials with this new treat have set the stage for larger studies in a wide range of cancers.