Curated Papers > Recent research on high-impact "CAR-T therapy" (IF≥30, last 5 years)

Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy.

Literature Information

DOI	10.1016/j.cell.2025.07.046
PMID	40845838
Journal	Cell
Impact Factor	42.5
JCR Quartile	Q1
Publication Year	2025
Times Cited	1
Keywords	CAR-T cell, activation-induced cell death, allogeneic immunity, genome-wide CRISPR screens, glycan
Literature Type	Journal Article, Clinical Trial, Phase I
ISSN	0092-8674
Pages	6317-6334.e21
Issue	188(22)
Authors	Zeguang Wu, Jinhong Shi, Qiezhong Lamao, Yuanyuan Qiu, Jinxin Yang, Yang Liu, Feifei Liang, Xue Sun, Wei Tang, Changya Chen, Qingming Yang, Chunmeng Wang, Zhifang Li, Haixia Zhang, Zhonghan Yang, Yunyi Zhang, Yuting Yi, Xufen Zheng, Yu Sun, Kuiying Ma, Lingling Yu, Huihui Yang, Zhaoxuan Wang, Wenjuan Zheng, Ling Yang, Zhixuan Zhang, Yongjian Zhang, Zhiqiang Wu, Yao Wang, Catherine C L Wong, Ming Jin, Pengfei Yuan, Weidong Han, Wensheng Wei

TL;DR

This study investigates the potential of deleting signal peptide peptidase-like 3 (SPPL3) to enhance glycan-mediated immune evasion in allogeneic CAR-T cell therapy, demonstrating that SPPL3-null, TCR-deficient anti-CD19 CAR-T cells can achieve safety in clinical trials while reducing allogeneic immunity without sacrificing functionality. The findings indicate that SPPL3 deletion may represent a novel strategy to improve the persistence and applicability of universal CAR-T therapies, particularly in the treatment of relapsed/refractory B cell non-Hodgkin lymphoma.

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CAR-T cell · activation-induced cell death · allogeneic immunity · genome-wide CRISPR screens · glycan

Abstract

Despite the success of autologous chimeric antigen receptor (CAR)-T cell therapy, achieving persistence and avoiding rejection in allogeneic settings remains challenging. We showed that signal peptide peptidase-like 3 (SPPL3) deletion enabled glycan-mediated immune evasion in primary T cells. SPPL3 deletion modified glycan profiles on T cells, restricted ligand accessibility, and reduced allogeneic immunity without compromising the functionality of anti-CD19 CAR molecules. In a phase I clinical trial, SPPL3-null, T cell receptor (TCR)-deficient anti-CD19 allogeneic CAR-T cells reached the safety primary endpoint, with grade 3 or higher cytokine release syndrome (CRS) observed in 3 out of 9 patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL) (ClinicalTrials.gov: NCT06014073). Reverse translational research highlighted the pivotal role of TCR in sustaining T cell persistence. We therefore evaluated the safety of SPPL3-null, TCR-sufficient CAR-T therapy on three patients with lymphoma or leukemia for compassionate care and observed no clinical signs of graft-versus-host disease. Our findings suggest glycan shielding by SPPL3 deletion is a promising direction for optimizing universal CAR-T therapies.

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Primary Questions Addressed

1. How does glycan shielding specifically influence the immune evasion mechanisms in allogeneic CAR-T therapies?
2. What are the potential long-term effects of SPPL3 deletion on T cell functionality and persistence in CAR-T therapies?
3. In what ways could the findings regarding SPPL3-null CAR-T cells be applied to enhance other forms of immunotherapy?
4. What additional strategies could be combined with glycan shielding to further improve the efficacy of CAR-T cell treatments?
5. How does the presence of TCR in SPPL3-null CAR-T cells affect the overall safety profile compared to TCR-deficient variants?

Key Findings

Research Background and Objectives

Chimeric antigen receptor (CAR)-T cell therapy has shown significant success in treating certain hematological malignancies. However, the persistence of CAR-T cells and their rejection in allogeneic settings remain significant challenges. This study aims to investigate the role of signal peptide peptidase-like 3 (SPPL3) deletion in facilitating glycan-mediated immune evasion in primary T cells, with the goal of improving the safety and efficacy of allogeneic CAR-T therapies.

Main Methods/Materials/Experimental Design

The study employed a combination of laboratory experiments and a phase I clinical trial to assess the effects of SPPL3 deletion on T cell functionality and allogeneic immunity.

Experimental Design Overview

1. SPPL3 Deletion: Primary T cells were genetically modified to delete SPPL3.
2. Glycan Profile Analysis: The glycan profiles of the modified T cells were analyzed to assess changes post-deletion.
3. Allogeneic Immunity Assessment: The immune response against the modified T cells was evaluated.
4. Phase I Clinical Trial: Conducted under ClinicalTrials.gov: NCT06014073, focusing on the safety of SPPL3-null, TCR-deficient anti-CD19 CAR-T cells in patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL).

Key Results and Findings

• Glycan Modification: SPPL3 deletion successfully altered the glycan profiles on T cells, leading to reduced allogeneic immune responses.
• Clinical Trial Outcomes: In the phase I trial, the SPPL3-null, TCR-deficient CAR-T cells met the primary safety endpoint. Notably, 3 out of 9 patients experienced grade 3 or higher cytokine release syndrome (CRS).
• Reverse Translational Research: This highlighted the importance of TCR in maintaining T cell persistence, leading to further evaluation of SPPL3-null, TCR-sufficient CAR-T therapy in compassionate care scenarios.

Main Conclusions/Significance/Innovation

The findings suggest that SPPL3 deletion facilitates glycan shielding, which significantly enhances the potential for universal CAR-T therapies by reducing the risk of allogeneic rejection while maintaining therapeutic functionality. This innovative approach could pave the way for safer and more effective CAR-T cell treatments, addressing a critical barrier in the field of immunotherapy.

Research Limitations and Future Directions

• Limitations: The study was limited by a small sample size in the clinical trial and the focus on a specific patient population (relapsed/refractory B-NHL).
• Future Directions: Further studies are warranted to explore the long-term effects of SPPL3 deletion in larger, more diverse patient cohorts. Additionally, investigating the combination of SPPL3 deletion with other immunomodulatory strategies could enhance CAR-T cell persistence and efficacy in various malignancies.

Aspect	Details
Study Focus	SPPL3 deletion in T cells for allogeneic CAR-T therapy
Key Findings	Glycan modification, reduced allogeneic immunity
Clinical Trial Results	Safety endpoint met, observed CRS in 3/9 patients
Research Implications	Potential for universal CAR-T therapies
Future Research Needs	Larger trials, combination therapies

Literatures Citing This Work

1. Advancing antivirals. - Nature biotechnology (2025)

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