CAR-T-Derived Extracellular Vesicles: A Promising Development of CAR-T Anti-Tumor Therapy

SIMPLE SUMMARY: In this review we aim to address the potential of extracellular vesicles stemming from chimeric antigen receptor T (CAR-T) lymphocytes as therapeutic agents in tumors. We underlined how CAR-T-lymphocytes, representing one of the new frontiers of immunotherapy for the fight against refractory neoplastic diseases, demonstrated their potential effectiveness in cancer. However, the presence of physical barriers that prevent the entry of CAR-T and other immune effector cells, the hostile microenvironment that hampers persistence and activity of immune cells, as well as tumor heterogeneity resulted in their variable or low efficacy against solid tumors. The application of CAR-T-derived extracellular vesicles as therapeutic agents may improve the homing of CAR-T effector functions through their facilitated diffusion within solid tumors and at the same time might circumvent some of the adverse effects that are induced by the cellular counterpart. ABSTRACT: Extracellular vesicles (EVs) are a heterogenous population of plasma membrane-surrounded particles that are released in the extracellular milieu by almost all types of living cells. EVs are key players in intercellular crosstalk, both locally and systemically, given that they deliver their cargoes (consisting of proteins, lipids, mRNAs, miRNAs, and DNA fragments) to target cells, crossing biological barriers. Those mechanisms further trigger a wide range of biological responses. Interestingly, EV phenotypes and cargoes and, therefore, their functions, stem from their specific parental cells. For these reasons, EVs have been proposed as promising candidates for EV-based, cell-free therapies. One of the new frontiers of cell-based immunotherapy for the fight against refractory neoplastic diseases is represented by genetically engineered chimeric antigen receptor T (CAR-T) lymphocytes, which in recent years have demonstrated their effectiveness by reaching commercialization and clinical application for some neoplastic diseases. CAR-T-derived EVs represent a recent promising development of CAR-T immunotherapy approaches. This crosscutting innovative strategy is designed to exploit the advantages of genetically engineered cell-based immunotherapy together with those of cell-free EVs, which in principle might be safer and more efficient in crossing biological and tumor-associated barriers. In this review, we underlined the potential of CAR-T-derived EVs as therapeutic agents in tumors.