[In vivo CAR-T cells: When the patient becomes their own factory]

Over the past decade, ex vivo autologous chimeric antigen receptor (CAR)-T cell therapies have profoundly reshaped the treatment of B-cell malignancies. Despite their remarkable clinical efficacy, their use remains limited by complex manufacturing processes, demanding logistics, long production times, and high costs. In vivo CAR-T approaches are emerging as a potential solution to overcome these obstacles by inducing CAR expression in T-cells directly within the patient's body. This overview provides a comprehensive look at the current development of these therapies. We describe the main delivery platforms under clinical investigation, focusing on lentiviral vectors (LVV) and lipid nanoparticles (LNP), and discuss their differences in terms of mechanisms of action, associated risks, and optimization strategies. We also summarize the key ongoing clinical trials evaluating in vivo CAR-T approaches in hematologic malignancies and autoimmune diseases. Finally, we highlight other in vivo CAR generation methods under development that may address remaining challenges.