CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells
Clinical application of autologous chimeric antigen receptor (CAR)-T cells is complicated by limited targeting of cancer types, as well as the time-consuming and costly manufacturing process. We develop CD70-targeted, induced pluripotent stem cell-derived CAR-natural killer (NK) (70CAR-iNK) cells as an approach for universal immune cell therapy. Besides the CD70-targeted CAR molecule, 70CAR-iNK cells are modified with CD70 gene knockout, a high-affinity non-cleavable CD16 (hnCD16), and an interleukin (IL)-15 receptor α/IL-15 fusion protein (IL15RF). Multi-gene-edited 70CAR-iNK cells exhibit robust cytotoxicity against a wide range of tumors. In vivo xenograft models further demonstrate their potency in effectively targeting lymphoma and renal cancers. Furthermore, we find that recipient alloreactive T cells express high levels of CD70 and can be eliminated by 70CAR-iNK cells, leading to improved survival and persistence of iNK cells. With the capability of tumor targeting and the potential to eliminate alloreactive T cells, 70CAR-iNK cells are potent candidates for next-generation universal immune cell therapy.
Authors
- Guolong Mo
- Linghui Zhou (ORCID: https://orcid.org/0000-0002-4524-6114)
- Zhuomao Mo (ORCID: https://orcid.org/0000-0002-4615-2216)
- Lihong Shen (ORCID: https://orcid.org/0009-0007-7439-8698)
- Yongxian Hu (ORCID: https://orcid.org/0009-0009-9154-0072)
- Wen Zeng (ORCID: https://orcid.org/0000-0002-8251-4624)
- Xiangjun He
- Mengqi Xu (ORCID: https://orcid.org/0000-0001-8264-7083)
- Yuxuan Shao
- Yanan Yue
- Linqin Wang (ORCID: https://orcid.org/0000-0001-6293-6742)
- Yixuan Zhou
- Kexin Wang (ORCID: https://orcid.org/0000-0001-9184-3967)
- Pengfei Zhang (ORCID: https://orcid.org/0000-0003-3470-085X)
- Xiaofeng Jia (ORCID: https://orcid.org/0000-0003-1445-8525)
- Yiyun Wang (ORCID: https://orcid.org/0000-0003-0775-4377)
- He Huang (ORCID: https://orcid.org/0000-0002-2723-1621)
- Nian Chen (ORCID: https://orcid.org/0000-0001-9804-5319)
- Dongrui Wang (ORCID: https://orcid.org/0000-0002-0859-7281)
- Xinghua Liang
- Luhan Yang (ORCID: https://orcid.org/0009-0006-0588-6551)
- Xiaobin Song
- Mengyu Zhao
- Ruimin Hong
- Youqin Feng
Institutions
- Hangzhou DAC Biotech (China) (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101889
- Citations
- 35
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 36.59
Funders
- National Natural Science Foundation of China
- Tsinghua University
- Sanming Project of Medicine in Shenzhen
- Science and Technology Department of Zhejiang Province