eVLP-mediated CREM editing enhances cytotoxicity of bicistronic IL-15-armored CD19/BCMA dual-target CAR-NK cells
- 1Shenzhen Cell Valley Biopharmaceuticals Group Co., Ltd. , ,
Abstract
Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells represent a promising platform for cancer immunotherapy; however, optimization of CAR architecture and additional engineering strategies remain necessary to improve their functional activity. In this study, we generated CD19/BCMA dual-target CAR constructs based on tandem and bicistronic configurations with or without membrane-bound interleukin-15 (mbIL-15), and further evaluated engineered virus-like particle (eVLP)-mediated CREM editing as an additional strategy for CAR-NK cell engineering. Four CAR configurations were evaluated in primary human T and NK cells for CAR expression, cytotoxicity, cytokine production, and proliferative activity. Bicistronic CD19/BCMA CAR-mbIL-15 cells exhibited enhanced functional activity compared with corresponding tandem CAR-mbIL-15 cells, including increased tumor-cell killing and activation-associated functional responses in vitro . In a CD19/BCMA-positive leukemia xenograft model, bicistronic CD19/BCMA CAR-mbIL-15 T and NK cells reduced tumor burden, delayed disease progression, and prolonged survival. Furthermore, eVLP-mediated CREM editing achieved efficient genome modification in primary NK cells and remained compatible with subsequent CAR engineering. CREM-edited CAR-NK cells exhibited increased cytotoxic activity compared with unedited CAR-NK cells in vitro . Collectively, these findings support the development of modular CAR-NK engineering strategies integrating CAR architecture optimization, membrane-bound cytokine armoring, and transient genome engineering.
Related
- AARS1‐Mediated RUNX3 K193 Lactylation Enhances the Activation and Cytotoxicity of CD8+T Cells in Smoking‐Related Emphysema
- GITRL COEXPRESSION IN ANTI-GD2 CAR-T CELLS ENHANCES RESISTANCE TO TREG-MEDIATED IMMUNOSUPPRESSION, MITIGATES EXHAUSTION, AND BOOSTS CYTOTOXICITY AGAINST GLIOBLASTOMA SPHEROIDS AND ORGANOTYPIC TUMOR SLICES
- BAM15 Enhances Regorafenib Cytotoxicity in a Canine Osteosarcoma Cell Model
- GLP1R agonists and vorasidenib converge on peroxynitrite-mediated cytotoxicity in mutant IDH glioma
- NIR-responsive cetuximab-functionalized chitosan-polydopamine hydrogel Co- delivering Ca²⁺ and gefitinib for EGFR-targeted esophageal cancer therapy via Ca²⁺- mediated cytotoxicity and potential immunomodulatory effects.
BibTeX
@article{shang2026evlpmediated,
title = {{eVLP-mediated CREM editing enhances cytotoxicity of bicistronic IL-15-armored CD19/BCMA dual-target CAR-NK cells}},
author = {Fengqin Shang and Guanlie Li and Shiting Gong and Lijiao Zhao and Bingyu Niu and Hanyi Chen and Yuchen Fu and Lijun Zhao and Jianxun Wang and Yuanyuan Shi},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1976202},
url = {https://europepmc.org/article/PMC/PMC13668854},
note = {CC BY},
}
RIS
TY - JOUR
TI - eVLP-mediated CREM editing enhances cytotoxicity of bicistronic IL-15-armored CD19/BCMA dual-target CAR-NK cells
AU - Fengqin Shang
AU - Guanlie Li
AU - Shiting Gong
AU - Lijiao Zhao
AU - Bingyu Niu
AU - Hanyi Chen
AU - Yuchen Fu
AU - Lijun Zhao
AU - Jianxun Wang
AU - Yuanyuan Shi
PY - 2026
DA - 2026/10/01
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1976202
UR - https://europepmc.org/article/PMC/PMC13668854
AB - Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells represent a promising platform for cancer immunotherapy; however, optimization of CAR architecture and additional engineering strategies remain necessary to improve their functional activity. In this study, we generated CD19/BCMA dual-target CAR constructs based on tandem and bicistronic configurations with or without membrane-bound interleukin-15 (mbIL-15), and further evaluated engineered virus-like particle (eVLP)-mediated CREM editing as an additional strategy for CAR-NK cell engineering. Four CAR configurations were evaluated in primary human T and NK cells for CAR expression, cytotoxicity, cytokine production, and proliferative activity. Bicistronic CD19/BCMA CAR-mbIL-15 cells exhibited enhanced functional activity compared with corresponding tandem CAR-mbIL-15 cells, including increased tumor-cell killing and activation-associated functional responses in vitro . In a CD19/BCMA-positive leukemia xenograft model, bicistronic CD19/BCMA CAR-mbIL-15 T and NK cells reduced tumor burden, delayed disease progression, and prolonged survival. Furthermore, eVLP-mediated CREM editing achieved efficient genome modification in primary NK cells and remained compatible with subsequent CAR engineering. CREM-edited CAR-NK cells exhibited increased cytotoxic activity compared with unedited CAR-NK cells in vitro . Collectively, these findings support the development of modular CAR-NK engineering strategies integrating CAR architecture optimization, membrane-bound cytokine armoring, and transient genome engineering.
SN - 1664-3224
ER -