# Non-human primate preclinical model revealed the feasibility and short-term safety of iPSC-derived innate-like T cells in autologous transplantation

## TL;DR

This study shows that iPSC-derived T cells can be safely transplanted into monkeys, offering a better preclinical model for testing immunotherapies.

## Contribution

The development of a non-human primate model for evaluating iPSC-derived T cells in autologous transplantation.

## Key findings

- iPSC-T cells showed antigen-dependent and -independent cytotoxicity and strong proliferative capacity.
- No safety issues were observed in macaques for one year after autologous iPSC-T cell infusions.
- Infused cells trafficked to the alveolar space and disappeared from circulation within seven days.

## Abstract

T cells derived from gene-edited induced pluripotent stem cells (iPSCs) are a promising alternative cell source for universal T-cell immunotherapy. However, current preclinical evaluations of iPSC-derived T cells (iPSC-T cells) rely on immunodeficient mouse models, which limit the assessment of immune-related adverse events and in vivo immune cell interactions.

To overcome these limitations, we developed a preclinical nonhuman primate model to evaluate the safety and cellular kinetics of iPSC-T cells. iPSCs were generated from peripheral blood T cells obtained from two rhesus macaques and redifferentiated in vitro into CD8αβ-CD3+ innate-like T cells. Phenotypic and functional characterization was performed using flow cytometric analyses. The proliferative capacity of iPSC-T cells was assessed by repeated stimulation with phytohemagglutinin (PHA), and cytotoxic function was evaluated through co-culture assays with target cells. The cells were further transduced with GFP using retroviral vectors during expansion. Autologous GFP⁺ iPSC-T cells were administered to the donor macaques in three separate infusions to assess in vivo safety and cellular kinetics.

The iPSC-T cells exhibited both antigen-dependent and antigen-independent cytotoxicity and demonstrated robust proliferative capacity upon repeated stimulation. Stable GFP expression was maintained during cell expansion. Following autologous infusion, no safety concerns were observed for up to one year after the first administration. Cellular kinetic analyses revealed that the infused iPSC-T cells trafficked to the alveolar space and were no longer detectable in peripheral circulation by seven days post-infusion.

These findings establish a unique immunocompetent primate model for assessing the safety and in vivo behavior of iPSC-T cells. This platform enables more physiologically relevant preclinical evaluation and supports the development of iPSC-derived T-cell immunotherapies for cancer and autoimmune diseases.