Reprogramming the Immune System to Target Cancer: Chimeric Antigen Receptor T-Cell Therapy

The immune system plays an important role in preventing tumor initiation and development. It can prevent tumor development by both protecting a person from infection with oncogenic viruses and through tumor surveillance, by which the immune system targets cells that abnormally express tumor antigens.¹ Cancer often develops when tumor cells evade immune surveillance or suppress the immune response, resulting in immune tolerance.^2,3

Cell-based immunotherapies that overcome immune tolerance by reprogramming the immune system to make it more targeted and effective at eliminating tumor cells have been developed. One such therapy employs chimeric antigen receptor (CAR) T-cells, which are reprogrammed T-cells that selectively identify tumor cells and target them for destruction. The therapy involves harvesting a patient’s T-cells, genetically reengineering the cells in a laboratory, then infusing the reprogrammed T-cells back into the patient to seek and destroy tumor cells.^4,5 In this article, we describe CAR T-cell therapy and the nurses’ role in caring for patients undergoing this therapy, based on our experience treating patients participating in CTL019 clinical studies. CTL019 is a CAR T-cell therapy being evaluated for the treatment of B-cell malignancies.

CARs are engineered fusion proteins consisting of an extracellular antigen-binding domain derived from an antibody and intracellular stimulatory domains. Second-generation CARs include an intracellular costimulatory region to enhance activation. A CAR therefore combines all of the cellular signaling components required to activate a T-cell. To express a CAR on a patient’s T-cells, the T-cells are harvested and genetically modified with a viral vector encoding the CAR.⁶ Several CAR T-cell therapies have been developed and clinically evaluated with a great deal of investigation directed at tumors that express CD19, a cell surface protein expressed in most B-cell malignancies including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and most B-cell lymphomas.^7,8 CTL019, a CD19-targeted CAR T-cell therapy developed at the University of Pennsylvania, has been in clinical investigations since 2010 and was the first CAR T-cell therapy to be given breakthrough therapy designation status by the US Food and Drug Administration.

Patients were consented and the risks associated with therapy are described prior to initiating the clinical trial; but given the complexities of the therapy, risks were also discussed throughout the clinical trial. Figure 1 illustrates the CTL019 therapy process.^6,9,10