CAR-T Cell Therapy for Pediatric Acute Lymphoblastic Leukemia
Immunotherapy is a treatment strategy that harnesses the natural ability of the body’s own immune cells to attack and kill tumor cells.
Immunotherapy is now considered as an important
“pillar” of cancer treatment. CAR-T cell therapy is a promising type of immunotherapy and is now approved for children and young adults with B-cell acute lymphoblastic leukemia (ALL)—the most common childhood cancer in the U.S, especially among patients whose cancers return after chemotherapy or a stem cell transplant.
The backbone of CAR T-cell therapy is the T cells that can create an immune response to a foreign invasion. CAR-T cells use the patient’s own immune cells to treat his or her cancer. The harvested T cells are genetically engineered to produce new surface proteins (the CARs, or Chimeric Antigen Receptors) that allow them to recognize and attack cancer cells more effectively.
These special receptors allow the T cells to recognize and attach to a specific protein, or antigen, on tumor cells. After expanding the number of these enhanced T cells, they can be infused back into patients to improve their immune systems. The engineered cells are able to further multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces. The CAR on the cell’s surface is composed of fragments, or domains, of synthetic antibodies. The domains that are used can affect how well the receptor recognizes or binds to the antigen on the tumor cell.
The receptors rely on stimulation signals such that each CAR T cell has signaling and “co-stimulatory” domains inside the cell that signal the cell from the surface receptor. The different domains that are used can affect the cells’ overall function. Over time, advances in the intracellular engineering of CAR T cells have improved the engineered T cells’ ability to produce more T cells after infusion into the patient (expansion) and survive longer in the circulation (persistence). Recent research has emerged to produce a batch of CAR T cells in a much shorter time; although it initially took several weeks, many labs have now reduced the time to less than 7 days.
Researchers believe that CAR T cells are the equivalent of “giving patients a living drug” and of promise in relapsed pediatric ALL.
However, like other forms of cancer therapies, radiation and chemotherapy, CART T cell therapy is not without side-effects. One of the most frequent and worrisome unwanted effect is cytokine release syndrome (CRS). T cells release cytokines, and in CRS, there is a rapid and massive release of cytokines into the bloodstream, which can lead to dangerously high fevers and precipitous drops in blood pressure. CRS is considered an “on-target” effect of CAR T-cell therapy and patients with the most extensive disease prior to receiving CAR T cells are more likely to experience severe CRS. Steroids and tocilizumab has become a standard therapy for managing severe CRS. A reversible form of cerebral edema has also been observed in some patients with CAR T cell therapy.