Chiba University and RIKEN establish master cell bank for immune cells generated from iPS cells — Safety confirmed and clinical trial shows signs of therapeutic efficacy

Professor Shinichiro Motohashi of the Graduate School of Medicine at Chiba University and Assistant Professor Tomohisa Iinuma of the Department of Otorhinolaryngology, Head and Neck Surgery at Chiba University Hospital, in collaboration with the RIKEN Center for Integrative Medical Sciences, announced on January 16 that they have confirmed safety and signs of therapeutic efficacy in a Phase 1 investigator-initiated clinical trial that directly administered immune cells called "iPSC-iNKT cells" generated from iPS cells to patients with head and neck squamous cell carcinoma. They confirmed stable supply of the cells through off-the-shelf allogeneic iPSC-iNKT cells. This is expected to lead to the development of treatment methods using these cells. The results were published in Nature Communications on December 30.

NKT cells are a type of T cell with characteristics of both NK cells and T cells. Although they constitute only 0.01% of blood cells, they exert powerful anti-tumor effects through antigen-presenting cells such as dendritic cells. NKT cells themselves directly attack cancer cells, and it is known that they also produce IFN-γ to activate T cells and NK cells to attack.

Until now, Chiba University has been working on clinical research targeting head and neck cancer by activating NKT cells in vivo or culturing and supplementing them with activation ex vivo. However, challenges have been identified, including the use of patients' autologous cells, variability in culture results, and high costs due to the custom-made nature of the treatment.

Therefore, in this study, they focused on the high proliferative capacity of iPS cells and aimed to develop a treatment method using "NKT cells (iPSC-iNKT cells)" derived from allogeneic NKT-iPS cells.

Research was initiated in 2013 to establish a master cell bank at the RIKEN Center for Integrative Medical Sciences. The researchers established a system for preparing off-the-shelf cells by obtaining iPS cells (NKT-iPS cells) from NKT cells derived from healthy adults and cryopreserving them; these are then thawed as needed, differentiated into NKT cells, expanded, and administered to patients. This enabled a stable supply of cells with guaranteed performance.

In the clinical trial, which took place from October 2020 to August 2023, "iPSC-iNKT cells" were administered to patients with recurrent or advanced head and neck squamous cell carcinoma who had completed standard treatment. The tolerability, safety, and efficacy of intra-arterial administration of "iPSC-iNKT cells" into tumor-feeding vessels were evaluated.

Twelve cases were registered in the clinical trial, and 10 cases participated after screening. "iPSC-iNKT cells" were administered via a catheter in the groin once to a maximum of three times at two-week intervals. Dose level 1 (3×10⁷ cells/m²) and dose level 2 (1×10⁸ cells/m²) were established, with dose level 1 administered to three cases and dose level 2 to seven cases. CT images were taken before the initial administration and on day 42, and eight cases were compared and evaluated between before the initial administration and day 42.

In terms of safety, the results showed that adverse events that could not be ruled out as related included anemia, fever, urticaria, and systemic rash. The most severe adverse event was one case of systemic rash that occurred at dose level 2, but it promptly resolved with steroid treatment. This suggested that the maximum tolerated dose was dose level 2.

Regarding efficacy, evaluation by CT imaging showed that tumor size was stable (growth rate ±10% or less) in five cases, with tumor reduction (-10%) observed in two of these cases. Progression was observed in three cases with a growth rate of 20% or more.

In one case where tumor reduction was observed, examination of PD1-positive CD8 T cells (cells that attack bacteria and cancer cells) in peripheral blood showed activation 8 days after administration. Single-cell analysis suggested that the gene groups elevated 8 days after administration were activated under the influence of IFN-γ released by the "iPSC-iNKT cells" administered.

Furthermore, when comparing CD8 T cells over time from before administration to day 21 after administration in the case with the greatest tumor growth and two cases with tumor reduction, the researchers found that CD8 T cells proliferated in the two reduction cases but did not increase in the one growth case.

In addition, when examining the properties of cytotoxic T cells in the two reduction cases, the researchers confirmed an increase in T cells that remember past antigen stimulation or already possess strong cytotoxicity.

Iinuma commented: "Based on these results, I believe we have opened a path toward utilizing off-the-shelf cancer immunotherapy. However, we believe the effects are not yet sufficient, and we are currently conducting and recruiting for a clinical trial at Chiba University Hospital combining dendritic cells loaded with NKT cell activators and iPSC-iNKT cells. The target is general head and neck cancer and cervical recurrence cases. With these results, we will continue to research and make efforts in cancer immunotherapy utilizing NKT cells."

Journal Information
Publication: Nature Communications
Title: Allogeneic iPSC-derived iNKT cells in recurrent head and neck cancer: a phase 1 trial
DOI: 10.1038/s41467-025-66801-w