An approach to regenerating exhausted T cells

Regenerating T cells through induced pluripotent stem cells (iPSCs) can increase their proliferative capacity while preserving their original antigen-recognition ability. The review by Wang and Kaneko in Inflammation and Regeneration describes how this approach is expanding from patient-specific cell regeneration toward premanufactured allogeneic therapies. It synthesizes the researchers’ earlier studies and development strategies rather than reporting a new efficacy trial in patients.

In chronic infections and advanced cancers, persistent antigen stimulation can impair T-cell proliferation and killing function. The review explains that starting-cell quality varies among patients, sometimes leading to manufacturing failures or reduced treatment efficacy. Preparing cells separately for each patient also entails costs and manufacturing delays.

The researchers developed a strategy to reprogram antigen-specific T cells into iPSCs and then differentiate them back into T cells. In early research on human immunodeficiency virus (HIV) antigen-specific T cells described in the review, the regenerated cells retained the original T-cell receptor (TCR) genes and antigen specificity while showing greater cytokine production and proliferative capacity than the starting cells. However, additional TCR gene rearrangement during redifferentiation caused some loss of antigen specificity. This prompted deletion of the RAG2 gene in subsequent research.

Designing culture, signaling, and receptors together

Manufacturing methods have progressed from reliance on mouse feeder cells toward conditions that use neither animal-derived components nor feeder cells. Delta-like ligand 4 (DL4) immobilized on the culture surface induces T-cell differentiation from hematopoietic progenitor cells, while cytokines are used to adjust proliferation conditions. Excluding animal-derived components is intended to manage contamination risk; it does not mean that all contamination risks are eliminated.

The strength of chimeric antigen receptor (CAR) signaling also affected differentiation. According to the review, antigen-independent signaling from some CD28-based CARs interfered with T-cell lineage differentiation, whereas 4-1BB-based designs provided comparatively controlled signaling. In a subcutaneous xenograft mouse model, iPSC-derived CAR T cells with deletion of both diacylglycerol kinase (DGK) α and ζ, which are involved in signal suppression, showed improved tumor suppression and survival outcomes compared with conventional iPSC-derived CAR T cells and peripheral blood-derived CAR T cells without those gene edits. This comparison is limited to preclinical results.

Allogeneic therapy uses cells derived from another person. Two distinct issues must be addressed: immune rejection, in which the host immune system attacks the administered cells, and graft-versus-host disease (GvHD), in which the administered immune cells attack host tissues. The review describes a strategy to reduce recognition by host T cells by eliminating human leukocyte antigen (HLA) class I and II expression through deletion of B2M and CIITA. However, even an early design incorporating additional edits intended to evade natural killer (NK) cells showed limitations during long-term co-culture or under conditions involving activated NK cells. Subsequent research proposed deleting the adhesion molecules ICAM-1 and CD58 to interfere with stable binding to NK cells.

The roles of synthetic receptors also differ. Mini-TCR was designed to provide T-cell developmental signals while omitting the variable region responsible for antigen recognition. In co-culture experiments with targets presenting the WT1 antigen, the synthetic TCR–antigen receptor (STAR) showed target recognition and greater antigen sensitivity than conventional CARs. These results do not establish the absence of toxicity to normal tissues or off-target risks from gene editing.

Long-term safety and manufacturing validation remain before clinical use

At the time the review was written, the T-cell candidate NJA-001 was in final preclinical validation, with clinical trials planned to begin in 2026. The phase 1 trial described in the paper as ongoing since 2021 is a separate study of glypican-3 (GPC3)-targeted CAR-iPSC-derived innate lymphoid and NK cells. It should not be mistaken for evidence of efficacy in patients for T-cell therapy.

The review also describes extending the approach to regulatory T-cell-like cells that suppress immune responses. Cells expressing an HLA-A2-targeting CAR suppressed weight loss and prolonged survival in a xenogeneic GvHD mouse model, but whether the regulatory lineage remains stable in a strongly inflammatory environment still requires validation. Anticancer T cells also require assessment of long-term function and safety, the risk of tumor formation from residual undifferentiated cells, and genomic stability. The transition to automated, closed, three-dimensional culture is another manufacturing challenge identified for future work.

The review focuses on the researchers’ own development pathway. Kaneko disclosed a conflict of interest as a founder, shareholder, and director of Shinobi Therapeutics, which is developing NJA-001.

For details, see the full Wang and Kaneko review and the paper DOI.