Transient T cell therapies.

Chimeric antigen receptor (CAR) T cell therapy has achieved clinical success in hematological malignancies, but its reliance on viral vectors and complex ex vivo manufacturing poses challenges related to safety, cost, and scalability. Next-generation strategies, including universal ("off-the-shelf") and in vivo CAR-T cell therapies, have emerged to address these limitations. The latter strategy employs targeted delivery systems to directly program patients' T cells in situ, bypassing ex vivo manipulation and offering a more streamlined, scalable, and safer therapeutic paradigm. The success of in vivo CAR-T cell therapy relies on targeted delivery systems. While engineered lentiviruses enable stable integration, non-viral vectors for transient CAR expression offer superior pharmacological control. This approach, exemplified by lipid nanoparticles in combination with mRNA, avoids risks of insertional mutagenesis and enables titratable, short-lived CAR expression, thereby enhancing safety management and suitability for applications beyond oncology. In this chapter, we first delineate the pharmacological imperative for transient CAR expression. Next, various delivery strategies are systematically reviewed, including ex vivo electroporation, in vivo non-viral systems, and engineered virus-like particles. Afterwards, we summarize the ongoing clinical trials of transient CAR-T cell therapy for oncology and non-oncology indications. Finally, we provide perspectives on the development of next-generation transient CAR-T cell therapies.