Review'Off-the-shelf' immunotherapy with iPSC-derived rejuvenated cytotoxic TÂ lymphocytes

- Cytotoxic T lymphocytes (CTLs) exposed continuously to viral or tumor antigens become exhausted.
- Antigen-specific CTLs can be generated from iPSCs established from the original CTLs.
- iPSC-derived functionally rejuvenated CTLs have an antitumor effect in vivo.
- Banking of T-iPSCs as a source of CTLs makes “off-the-shelf” therapy feasible.
- The iC9-based suicide system provides a safeguard for rejuvenated CTL therapy.

Adoptive T-cell therapy to target and kill tumor cells shows promise and induces durable remissions in selected malignancies. However, for most cancers, clinical utility is limited. Cytotoxic T lymphocytes continuously exposed to viral or tumor antigens, with long-term expansion, may become unable to proliferate (“exhausted”). To exploit fully rejuvenated induced pluripotent stem cell (iPSC)-derived antigen-specific cytotoxic T lymphocytes is a potentially powerful approach. We review recent progress in engineering iPSC-derived T cells and prospects for clinical translation. We also describe the importance of introducing a suicide gene safeguard system into adoptive T-cell therapy, including iPSC-derived T-cell therapy, to protect from unexpected events in first-in-humans clinical trials.