Immune-evading universal donor iPSC-derived natural killer cells enable off-the-shelf cancer immunotherapy
- 1Research, Universal Cells, Inc.
- 2Research, Astellas Institute for Regenerative Medicine
Abstract
Background: Natural killer (NK) cells are a promising modality for cancer immunotherapy due to their intrinsic ability to eliminate malignant cells and their safety profile, while their clinical application remains limited by donor variability, immune rejection, and challenges in large-scale manufacturing.
Methods: We developed a multi–gene-edited universal donor induced pluripotent stem cell (iPSC)-derived NK cell (UDC-NK) platform. First, the engineered iPSC line was generated by disrupting B2M and RFXANK to eliminate HLA class I and II molecules and by introducing a single-chain HLA-E for immune evasion. In addition, a safety switch system was incorporated to ensure controllability. We also developed a novel feeder-free, scalable manufacturing process for cryopreserved UDC-NK cells for off-the-shelf cellular therapy.
Results: We succeeded in generating large numbers of UDC-NK cells with an activated phenotype. UDC-NK cells exhibited robust cytotoxicity and cytokine production against CD20 ⁺ lymphoma cell lines in vitro , which were further enhanced in the presence of Rituximab. UDC-NK cells effectively demonstrated immune evasion from allogeneic T cell– and NK cell–mediated responses. In addition, UDC-NK cells could be selectively eliminated via a herpes simplex virus thymidine kinase–based safety switch upon ganciclovir treatment in vitro . In disseminated B-cell lymphoma models, combination treatment with UDC-NK cells and Rituximab resulted in near-complete tumor growth inhibition and significantly prolonged survival.
Conclusions: These findings establish UDC-NK cells as a scalable off-the-shelf cell therapy platform with enhanced anti-tumor efficacy and built-in safety control, supporting their potential clinical application in combination with antibody-based cancer therapies.
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BibTeX
@article{ito2026immuneevading,
title = {{Immune-evading universal donor iPSC-derived natural killer cells enable off-the-shelf cancer immunotherapy}},
author = {Masayuki Ito and Hirofumi Tsuzuki and Michael A. Secinaro and Shannon Kreuser and Kaori Oda and Borith Kheng and Louie Galitan and Julie A. Vergara and Ippei Takeuchi and Sarah L. Ameny and Mary G. Prieve and Mark T. Orr and Taku Yoshida},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1938206},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1938206/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immune-evading universal donor iPSC-derived natural killer cells enable off-the-shelf cancer immunotherapy
AU - Masayuki Ito
AU - Hirofumi Tsuzuki
AU - Michael A. Secinaro
AU - Shannon Kreuser
AU - Kaori Oda
AU - Borith Kheng
AU - Louie Galitan
AU - Julie A. Vergara
AU - Ippei Takeuchi
AU - Sarah L. Ameny
AU - Mary G. Prieve
AU - Mark T. Orr
AU - Taku Yoshida
PY - 2026
DA - 2026/10/29
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1938206
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1938206/full
AB - Background: Natural killer (NK) cells are a promising modality for cancer immunotherapy due to their intrinsic ability to eliminate malignant cells and their safety profile, while their clinical application remains limited by donor variability, immune rejection, and challenges in large-scale manufacturing. Methods: We developed a multi–gene-edited universal donor induced pluripotent stem cell (iPSC)-derived NK cell (UDC-NK) platform. First, the engineered iPSC line was generated by disrupting B2M and RFXANK to eliminate HLA class I and II molecules and by introducing a single-chain HLA-E for immune evasion. In addition, a safety switch system was incorporated to ensure controllability. We also developed a novel feeder-free, scalable manufacturing process for cryopreserved UDC-NK cells for off-the-shelf cellular therapy. Results: We succeeded in generating large numbers of UDC-NK cells with an activated phenotype. UDC-NK cells exhibited robust cytotoxicity and cytokine production against CD20 ⁺ lymphoma cell lines in vitro , which were further enhanced in the presence of Rituximab. UDC-NK cells effectively demonstrated immune evasion from allogeneic T cell– and NK cell–mediated responses. In addition, UDC-NK cells could be selectively eliminated via a herpes simplex virus thymidine kinase–based safety switch upon ganciclovir treatment in vitro . In disseminated B-cell lymphoma models, combination treatment with UDC-NK cells and Rituximab resulted in near-complete tumor growth inhibition and significantly prolonged survival. Conclusions: These findings establish UDC-NK cells as a scalable off-the-shelf cell therapy platform with enhanced anti-tumor efficacy and built-in safety control, supporting their potential clinical application in combination with antibody-based cancer therapies.
SN - 1664-3224
ER -