NKT-Licensed In Vivo Dendritic Cell-Based Immunotherapy as Cellular Immunodrugs for Cancer Treatment

With the advent of new therapies, immunotherapy has gained attention as a critical modality. After the discovery of the natural killer T (NKT) cells ligand, <i>ex vivo</i> cultured dendritic cells (DCs) loaded with NKT ligand (especially &alpha;-galactosylceramide (&alpha;-GalCer) (DC/Gal) or <i>ex vivo</i> expanded NKT transfer studies were clinically examined in several institutes. To prevent tumoral immune escape, the link between innate and adaptive immunity, <i>in situ </i>selective targeting of DCs has been attempted; however, protocol optimization was required. As a type of DC targeting therapy that combines the benefits of invariant natural killer T (iNKT) cells, we established an all-in-one, off-the-shelf drug, named the artificial adjuvant vector cell (aAVC), which consists of the tumor antigen and the CD1d-iNKT ligand complex. Here, to our knowledge, we first demonstrate the DC/GalCer therapy and NKT transfer therapy. Next, we introduce and discuss the use of aAVC therapy not only for efficient innate and adaptive immunity induction using fully matured DC <i>in situ</i> but also the characterization necessary for locally reprogramming the tumor microenvironment and systemically inducing long-term memory in T cells. We also discuss how the immune network mechanism is controlled by DCs. Next, we performed the first human clinical trial using WT1 antigen-expressing aAVC against relapse and refractory acute myelogenous leukemia. Thus, we highlight the challenges of using aAVCs as prodrugs for actively energizing DCs <i>in vivo,</i> underpinning immunological networks, and developing strategies for providing maximal benefits for patients.