Finding your CAR: The road ahead for engineered T-cells

Adoptive cellular therapy using chimeric antigen receptors (CAR) has transformed immunotherapy by engineering T cells to target specific antigens on tumor cells. As the field continues to advance, pathology laboratories will play increasingly essential roles in the complicated multi-step process of CAR-T therapy. These include the detection of targetable tumor antigens by flow cytometry or immunohistochemistry at the time of disease diagnosis and the isolation and infusion of CAR-T cells. Additional roles include (1) detecting antigen loss or heterogeneity that renders resistance to CAR-T as well as identifying alternative targetable antigens on tumor cells, (2) monitoring the phenotype, persistence and tumor infiltration properties of CAR T-cells and the tumor microenvironment for factors that predict CAR-T success, and (3) evaluating side effects and biomarkers of CAR-T cytotoxicity such as cytokine release syndrome. In this review, we highlight existing technologies that are applicable to monitoring of CAR-T cell persistence, target antigen identification and loss. We also discuss emerging technologies that address new challenges, such as how to put a brake on CAR T-cells. While pathology laboratories have already provided companion diagnostic tests important in immunotherapy such as PD-L1, MSI, and HER2 testing, we draw attention to the exciting new translational research opportunities in adoptive cellular therapy.