Wensheng Wei and Weidong Han Teams Develop a Novel “Glycan Shielding” Strategy for Universal Cell Therapy
Source：Wensheng Wei
2025-11-26
On August 21, 2025, the teams led by Prof. Wensheng Wei at Peking University, the team led by Prof. Weidong Han at the General Hospital of the People’s Liberation Army, together with EdiGene, published a research article in Cell titled “Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy.” Through genome-wide functional screening, the study identified SPPL3 as a key gene that remodels glycosylation on the T-cell surface and proposed an innovative “glycan shielding” strategy, providing a new conceptual and technical framework for next-generation universal CAR-T therapies.
Although autologous CAR-T therapies have demonstrated remarkable efficacy in hematologic malignancies, their highly individualized manufacturing process leads to long production times, high costs, and frequent challenges in obtaining high-quality T cells from severely ill patients. Consequently, developing “off-the-shelf” allogeneic CAR-T products from healthy donors has become an important direction. However, allogeneic T cells face two major hurdles after GvHD and rapid clearance by the host immune system, which severely limit cellular persistence and therapeutic durability.
To address these challenges, the research team performed genome-wide CRISPR screening to systematically identify factors that enhance immune tolerance of allogeneic T cells. The screen revealed that SPPL3 knockout markedly increases surface glycan modification, generating a protective structure resembling a “glycan shield.” This “shield” functions by masking HLA molecules, reducing exposure of NK-cell activating ligands, and suppressing Fas/FasL-mediated apoptosis, thereby attenuating host immune attack without compromising the intrinsic antitumor activity of CAR-T cells.
Building on these findings, the investigators launched an investigator-initiated clinical trial (IIT) to assess the clinical feasibility of this strategy. In early studies, SPPL3 and TCR were simultaneously disrupted to avoid GvHD; however, this approach resulted in limited persistence in vivo, suggesting that preserving the endogenous TCR is essential for the long-term T-cell survival. In subsequent clinical testing, the team modified the strategy by knocking out SPPL3 while preserving TCR expression. The clinical outcomes showed that these engineered CAR-T cells persisted for more than six months without inducing classical GvHD or severe immune-related toxicities, and several patients achieved durable clinical responses. These results demonstrate that the combination of SPPL3 knockout with TCR preservation offers a viable and effective approach to improving the persistence and safety of allogeneic CAR-T therapies.
In summary, this study verifies the feasibility of the “glycan shielding” strategy from mechanistic discovery through clinical evaluation, establishing a new design principle for TCR-sufficient universal CAR-T cell therapies. Because this strategy targets glycosylation, a fundamental regulatory layer, it may be broadly applicable to γδ T cells, NK cells, and iPSC-derived immune cells, providing a powerful framework for universal engineering of multiple “off-the-shelf” cell therapies and accelerating their translation into clinical use.
The corresponding authors of the study are Prof. Wensheng Wei (Peking University), Prof. Weidong Han (PLA General Hospital), and Dr. Pengfei Yuan (EdiGene). Co-first authors include Dr. Zeguang Wu, Jinhong Shi, Dr. Qiezhong Lamao, Yuanyuan Qiu, Jinxin Yang, Dr. Yang Liu, and Dr. Feifei Liang. The study was supported by grants from the National Natural Science Foundation of China, the Ministry of Science and Technology Key R&D Program, the Major Chronic Non-communicable Disease Science and Technology Project, the CAMS Medical and Health Technology Innovation Fund, the CAMS Talent Program, the Peking-Tsinghua Center for Life Sciences, and the Changping Laboratory.
Article Link: https://www.sciencedirect.com/science/article/pii/S0092867425009109
Although autologous CAR-T therapies have demonstrated remarkable efficacy in hematologic malignancies, their highly individualized manufacturing process leads to long production times, high costs, and frequent challenges in obtaining high-quality T cells from severely ill patients. Consequently, developing “off-the-shelf” allogeneic CAR-T products from healthy donors has become an important direction. However, allogeneic T cells face two major hurdles after GvHD and rapid clearance by the host immune system, which severely limit cellular persistence and therapeutic durability.
To address these challenges, the research team performed genome-wide CRISPR screening to systematically identify factors that enhance immune tolerance of allogeneic T cells. The screen revealed that SPPL3 knockout markedly increases surface glycan modification, generating a protective structure resembling a “glycan shield.” This “shield” functions by masking HLA molecules, reducing exposure of NK-cell activating ligands, and suppressing Fas/FasL-mediated apoptosis, thereby attenuating host immune attack without compromising the intrinsic antitumor activity of CAR-T cells.
Building on these findings, the investigators launched an investigator-initiated clinical trial (IIT) to assess the clinical feasibility of this strategy. In early studies, SPPL3 and TCR were simultaneously disrupted to avoid GvHD; however, this approach resulted in limited persistence in vivo, suggesting that preserving the endogenous TCR is essential for the long-term T-cell survival. In subsequent clinical testing, the team modified the strategy by knocking out SPPL3 while preserving TCR expression. The clinical outcomes showed that these engineered CAR-T cells persisted for more than six months without inducing classical GvHD or severe immune-related toxicities, and several patients achieved durable clinical responses. These results demonstrate that the combination of SPPL3 knockout with TCR preservation offers a viable and effective approach to improving the persistence and safety of allogeneic CAR-T therapies.
In summary, this study verifies the feasibility of the “glycan shielding” strategy from mechanistic discovery through clinical evaluation, establishing a new design principle for TCR-sufficient universal CAR-T cell therapies. Because this strategy targets glycosylation, a fundamental regulatory layer, it may be broadly applicable to γδ T cells, NK cells, and iPSC-derived immune cells, providing a powerful framework for universal engineering of multiple “off-the-shelf” cell therapies and accelerating their translation into clinical use.
The corresponding authors of the study are Prof. Wensheng Wei (Peking University), Prof. Weidong Han (PLA General Hospital), and Dr. Pengfei Yuan (EdiGene). Co-first authors include Dr. Zeguang Wu, Jinhong Shi, Dr. Qiezhong Lamao, Yuanyuan Qiu, Jinxin Yang, Dr. Yang Liu, and Dr. Feifei Liang. The study was supported by grants from the National Natural Science Foundation of China, the Ministry of Science and Technology Key R&D Program, the Major Chronic Non-communicable Disease Science and Technology Project, the CAMS Medical and Health Technology Innovation Fund, the CAMS Talent Program, the Peking-Tsinghua Center for Life Sciences, and the Changping Laboratory.
Article Link: https://www.sciencedirect.com/science/article/pii/S0092867425009109
