Efficient Regeneration of Human Vα24+ Invariant Natural Killer T Cells and Their Anti-Tumor Activity In Vivo

Abstract

Reprogramming of antigen-specific T lymphocytes into induced pluripotent stem cells (iPSCs) and their subsequent re-differentiation has enabled expansion of functional T lymphocytes in vitro, thus opening up new approaches for immunotherapy of cancer and other diseases. In this study, we have established a robust protocol to reprogram human invariant NKT (Vα24 iNKT) cells, which have been shown to act as cellular adjuvants and thus exert anti-tumor activity in mice and humans, and to re-differentiate the iNKT cell-derived iPSCs into functional iNKT cells. These iPSC-derived iNKT cells (iPS-Vα24 iNKT cells) can be activated by ligand-pulsed dendritic cells (DCs) and produce a large amount of interferon-γ upon activation, as much as parental Vα24 iNKT cells, but exhibit even better cytotoxic activity against various tumor cell lines. The iPS-Vα24 iNKT cells possess significant anti-tumor activity in tumor-bearing mice and can activate autologous NK cells upon activation by ligand-pulsed DCs in the NOG mouse model in vivo, further extending their therapeutic potential. This study thus provides a first proof of concept for the clinical application of human iPS-Vα24 iNKT cells for cancer immunotherapy. Stem Cells 2016;34:2852-2860.

Enhancement of Adjuvant Functions of Natural Killer T Cells Using Nanovector Delivery Systems: Application in Anticancer Immune Therapy

“…This approach may provide potent antitumor activity (40, 41). Moreover, the reprogramming of NKT cells to induced pluripotent stem cells and their subsequent re-differentiation into more functional NKT cells (compared with the parental cells) is opening up new avenues in this field (42, 43). Another reason that might explain disappointing clinical data relates to the uncontrolled delivery of α-GalCer, which might lead to suboptimal primary and secondary activation of NKT cells.…”

Regeneration of CD8αβ T Cells from T-cell–Derived iPSC Imparts Potent Tumor Antigen-Specific Cytotoxicity

“…In keeping with this idea, we have recently succeeded in regenerating MART1-specific CTLs from iPSCs originally derived from CTLs of a melanoma patient (14). Other groups also have regenerated viral antigen-specific T cells (15,16), T cells expressing an invariant TCRs (17)(18)(19), and T cells that were genetically engineered to express a so-called chimeric antigen receptor (CAR; ref. 20).…”

One method to establish Epstein‐Barr virus‐associated NK/T cell lymphoma mouse models

“…On the other hand, even if the models are established successfully, they remain not stable in passages, or never have been passaged. So far, only some Japanese established SNK6‐which is a NK/T cell lymphoma cell line‐mouse model in NOG mice, which is a similar species to NSG . It is known that using NSG and NOG mice to establish models costs too much, meanwhile because of the patent problem, many enthusiastic researchers have not the opportunity to use them.…”

“…18,19 These mice to NSG. 24,25 It is known that using NSG and NOG mice to establish models costs too much, meanwhile because of the patent problem, many enthusiastic researchers have not the opportunity to use them.…”