The impressive development of cancer immunotherapy in the last few years originates from a more precise understanding of control mechanisms in the immune system leading to the discovery of new targets and new therapeutic tools. Since different stages of disease progression elicit different local and systemic inflammatory responses, the ability to longitudinally interrogate the migration and expansion of immune cells throughout the whole body will greatly facilitate disease characterization and guide selection of appropriate treatment regiments. While using radiolabeled white blood cells to detect inflammatory lesions has been a classical nuclear medicine technique for years, new non-invasive methods for monitoring the distribution and migration of biologically active cells in living organisms have emerged. They are designed to improve detection sensitivity and allow for a better preservation of cell activity and integrity. These methods include the monitoring of therapeutic cells but also of all cells related to a specific disease or therapeutic approach. Labeling of therapeutic cells for imaging may be performed in vitro, with some limitations on sensitivity and duration of observation. Alternatively, in vivo cell tracking may be performed by genetically engineering cells or mice so that may be revealed through imaging. In addition, SPECT or PET imaging based on monoclonal antibodies has been used to detect tumors in the human body for years. They may be used to detect and quantify the presence of specific cells within cancer lesions. These methods have been the object of several recent reviews that have concentrated on technical aspects, stressing the differences between direct and indirect labeling. They are briefly described here by distinguishing ex vivo (labeling cells with paramagnetic, radioactive, or fluorescent tracers) and in vivo (in vivo capture of injected radioactive, fluorescent or luminescent tracers, or by using labeled antibodies, ligands, or pre-targeted clickable substrates) imaging methods. This review focuses on cell tracking in specific therapeutic applications, namely cell therapy, and particularly CAR (Chimeric Antigen Receptor) T-cell therapy, which is a fast-growing research field with various therapeutic indications. The potential impact of imaging on the progress of these new therapeutic modalities is discussed.

PD-L1 (programmed death-ligand 1, B7-H1, CD274), the ligand for PD-1 inhibitory receptor, is expressed on various tumors, and its expression is correlated with a poor prognosis in melanoma. Anti-PD-L1 mAbs have been developed along with anti-CTLA-4 and anti-PD-1 antibodies for immune checkpoint inhibitor (ICI) therapy, and anti-PD-1 mAbs are now used as first line treatment in melanoma. However, many patients do not respond to ICI therapies, and therefore new treatment alternatives should be developed. Because of its expression on the tumor cells and on immunosuppressive cells within the tumor microenvironment, PD-L1 represents an interesting target for targeted alpha-particle therapy (TAT). We developed a TAT approach in a human melanoma xenograft model that stably expresses PD-L1 using a 213Bi-anti-human-PD-L1 mAb. Unlike treatment with unlabeled anti-human-PD-L1 mAb, TAT targeting PD-L1 significantly delayed melanoma tumor growth and improved animal survival. A slight decrease in platelets was observed, but no toxicity on red blood cells, bone marrow, liver or kidney was induced. Anti-tumor efficacy was associated with specific tumor targeting since no therapeutic effect was observed in animals bearing PD-L1 negative melanoma tumors. This study demonstrates that anti-PD-L1 antibodies may be used efficiently for TAT treatment in melanoma.