Dynamic imaging for CAR-T-cell therapy

Abstract

Abstract Chimaeric antigen receptor (CAR) therapy is entering the mainstream for the treatment of CD19 + cancers. As is does we learn more about resistance to therapy and the role, risks and management of toxicity. In solid tumour CAR therapy research the route to the clinic is less smooth with a wealth of challenges facing translating this, potentially hugely valuable, therapeutic option for patients. As we strive to understand our successes, and navigate the challenges, having a clear understanding of how adoptively transferred CAR-T-cells behave in vivo and in human trials is invaluable. Harnessing reporter gene imaging to enable detection and tracking of small numbers of CAR-T-cells after adoptive transfer is one way by which we can accomplish this. The compatibility of certain reporter gene systems with tracers available routinely in the clinic makes this approach highly useful for future appraisal of CAR-T-cell success in humans. This review covers the research to date in reporter gene imaging of gene-modified T-cells. Chimaeric antigen receptors (CARs) are membranespanning fusion molecules in which a targeting moiety, usually a single chain antibody fragment, is coupled via hinge and transmembrane elements to an activating endodomain. CARs can be transduced into human T-cells, via retroviral or lentiviral vectors, with the potential for co-expression of other genes. When expressed in T-cells CARs redirect their specificity against a designated native 'antigen', obviating the need for either HLA expression or antigen processing. Immunotherapy using CAR-engineered T-cells is acquiring an increasing niche in the experimental therapy of malignant disease [1]. Recent spectacular results have been achieved in the treatment of CD19 + haematologic malignancies + acute lymphoid leukaemia (ALL) Key words: CAR-T-cells, dynamic imaging, PET-CT, reporter genes, SPECT-CT. Abbreviations: CT, computed tomography; CAR, chimaeric antigen receptor; D2R, dopamine type 2-receptor; hdCKDM, human deoxycytidine kinase double mutant; hNET, human noradrenaline transporter gene; hNIS, human sodium iodide symporter; hSSTr2, human somatostatin receptor subtype 2; HSV-tk, herpes simplex virus thymidine kinase; h TK2DM, truncated and mutated human mitochondrial thymidine kinase 2; MIBG, metaiodobenzylguanidine; PET, positron emission tomography; SPECT, single photon emission computed tomography