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Chimeric antigen receptor T cell therapy (CAR-T) has been rolled out as a new treatment for hematological malignancies. For solid tumor treatment, CAR-T has been disappointing so far. Challenges include the quantification of CAR-T trafficking, expansion and retention in tumors, activity at target sites, toxicities, and long-term CAR-T survival. Non-invasive serial in vivo imaging of CAR-T using reporter genes can address several of these challenges. For clinical use, a non-immunogenic reporter that is detectable with exquisite sensitivity by positron emission tomography (PET) using a clinically available non-toxic radiotracer would be beneficial. Here, we employed the human sodium iodide symporter to non-invasively quantify tumor retention of pan-ErbB family targeted CAR-T by PET. We generated and characterized traceable CAR T cells and examined potential negative effects of radionuclide reporter use. We applied our platform to two different triplenegative breast cancer (TNBC) models and unexpectedly observed pronounced differences in CAR-T tumor retention by PET/CT (computed tomography) and confirmed data ex vivo. CAR-T tumor retention inversely correlated with immune checkpoint expression in the TNBC models. Our platform enables highly sensitive non-invasive PET tracking of CAR-T thereby addressing a fundamental unmet need in CAR-T development and offering to provide missing information needed for future clinical CAR-T imaging.

The clinical application of ex vivo gene edited cell therapies first began a decade ago with zinc finger nuclease editing of autologous CD4+ T‐cells. Editing aimed to disrupt expression of the human immunodeficiency virus co‐receptor gene CCR5, with the goal of yielding cells resistant to viral entry, prior to re‐infusion into the patient. Since then the field has substantially evolved with the arrival of the new editing technologies transcription activator‐like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR), and the potential benefits of gene editing in the arenas of immuno‐oncology and blood disorders were quickly recognised. As the breadth of cell therapies available clinically continues to rise there is growing interest in allogeneic and off‐the‐shelf approaches and multiplex editing strategies are increasingly employed. We review here the latest clinical trials utilising these editing technologies and consider the applications on the horizon.

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