Lipid nanoparticles outperform electroporation in mRNA-based CAR T cell engineering

被引：45

作者：

Kitte, Reni ^{[1
]}

Rabel, Martin ^{[2
]}

Geczy, Reka ^{[2
]}

Park, Stella ^{[2
]}

Fricke, Stephan ^{[1
,3
]}

Koehl, Ulrike ^{[1
,3
,4
]}

Tretbar, U. Sandy ^{[1
,3
]}

机构：

[1] Fraunhofer Inst Cell Therapy & Immunol IZI, Perlickstr 1, D-04103 Leipzig, Germany

[2] Precis NanoSyst Inc, Cytiva, 50-655 W Kent Ave N, Vancouver, BC V6P 6T7, Canada

[3] Fraunhofer Cluster Excellence Immune Mediated Dis, D-04103 Leipzig, Germany

[4] Univ Leipzig, Inst Clin Immunol, Med Fac, Johannisallee 30, D-04103 Leipzig, Germany

来源：

MOLECULAR THERAPY METHODS & CLINICAL DEVELOPMENT | 2023年 / 31卷

关键词：

4-1BB COSTIMULATION; DELIVERY; IMMUNOTHERAPY;

D O I：

10.1016/j.omtm.2023.101139

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Engineered T cells expressing chimeric antigen receptors (CARs) have been proven as efficacious therapies against selected hema-tological malignancies. However, the approved CAR T cell ther-apeutics strictly rely on viral transduction, a time-and cost-inten-sive procedure with possible safety issues. Therefore, the direct transfer of in vitro transcribed CAR-mRNA into T cells is pur-sued as a promising strategy for CAR T cell engineering. Electro-poration (EP) is currently used as mRNA delivery method for the generation of CAR T cells in clinical trials but achieving only poor anti-tumor responses. Here, lipid nanoparticles (LNPs) were examined for ex vivo CAR-mRNA delivery and compared with EP. LNP-CAR T cells showed a significantly prolonged effi- cacy in vitro in comparison with EP-CAR T cells as a result of extended CAR-mRNA persistence and CAR expression, attrib-uted to a different delivery mechanism with less cytotoxicity and slower CAR T cell proliferation. Moreover, CAR expression and in vitro functionality of mRNA-LNP-derived CAR T cells were comparable to stably transduced CAR T cells but were less exhausted. These results show that LNPs outperform EP and un-derline the great potential of mRNA-LNP delivery for ex vivo CAR T cell modification as next-generation transient approach for clinical studies.

引用

页数：12

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