In situ engineering of mRNA-CAR T cells using spleen-targeted ionizable lipid nanoparticles to eliminate cancer cells

被引:7
作者
Li, Yuan [1 ,2 ]
Tian, Yishi [1 ,2 ]
Li, Chanjuan [1 ,2 ]
Fang, Wenli [1 ,2 ]
Li, Xiaohong [1 ,2 ]
Jing, Zhangyan [1 ,2 ]
Yang, Zhaoxin [1 ,2 ]
Zhang, Xiaozhou [1 ,2 ]
Huang, Yanlan [1 ,2 ]
Gong, Jiaqi [4 ]
Meng, Fanqiang [1 ,2 ]
Qi, Lin [1 ,2 ]
Liang, Xin [3 ]
Hou, Linlin [1 ,2 ]
Lv, Kai [4 ]
Zhang, Xudong [1 ,2 ]
机构
[1] Sun Yat Sen Univ, Sch Med, Shenzhen Key Lab Syst Med Inflammatory Dis, Shenzhen Campus Sun Yat Sen Univ, Shenzhen 518107, Guangdong, Peoples R China
[2] Sun Yat Sen Univ, Mol Canc Res Ctr, Sch Med, Dept Pharmacol, Shenzhen Campus Sun Yat Sen Univ, Shenzhen 518107, Guangdong, Peoples R China
[3] Guangdong Med Univ, Dept Physiol, Guangdong Prov Key Lab Med Mol Diagnost, Dongguan 523808, Guangdong, Peoples R China
[4] Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biotechnol, Beijing 100050, Peoples R China
关键词
CAR T cells; mRNA-LNPs; Interleukin-7; Checkpoint blockade; Cancer immunotherapy; CYTOKINE RELEASE SYNDROME; B-CELLS; EXPRESSION; THERAPEUTICS; THERAPY; TYROSINASE; KNOCKDOWN; SURVIVAL; DELIVERY; IL-7;
D O I
10.1016/j.nantod.2024.102518
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Chimeric antigen receptor (CAR) T cell therapy has implemented impressive advances in the treatment of B-cell lymphoma. However, the complex production process of CAR T cells and hindrance of solid tumor penetration remain substantial challenges. Intriguingly, cell-targeting delivery of messenger RNA (mRNA) with ionizable lipid nanoparticles (mRNA-LNPs) is able to efficiently and precisely engineer T cells and other immune cells in vivo to perform their functions. Herein, we harnessed the ionizable LNPs to encapsulate mRNA encoding antityrosinase related protein 1 (TRP1) CAR (CAR-LNPs) for in vivo generation of mRNA-CAR T cells to eliminate melanoma cells. Specifically, the anti-CD3 antibody (aCD3) armed mRNA-LNPs (CD3-mRNA-LNPs) selectively targeted T cells, resulting in the production of functional and therapeutic levels of CAR T cells both ex vivo and in vivo. These CD3-CAR-LNPs engineered CAR T cells were capable of infiltrating into the solid tumor and effectively eliminating melanoma cells with high TRP1 expression, significantly hindering tumor progression. Critically, CD3-7CAR-LNPs containing mRNA encoding both CAR and interleukin-7 (IL-7) generated 7CAR T cells that secreted IL-7, thereby enhancing the activity and proliferation of both CAR T cells and other intratumoral cytotoxic T cells. Alternatively, the employment of anti-programmed cell death protein 1 antibody (aPD-1) protected mRNA-CAR T cells from exhaustion, especially in combination with CD3-7CAR-LNPs, could significantly enhance the antitumor capability of CAR T cells without causing acute cytokine release syndrome (CRS).
引用
收藏
页数:18
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