Lipid Nanoparticles Outperform Electroporation in MRNA-based CAR T cell Engineering

Overview

Journal Mol Ther Methods Clin Dev

Publisher Cell Press

Date 2023 Nov 29

PMID 38027056

Authors

Reni Kitte

Martin Rabel

Reka Geczy

Stella Park

Stephan Fricke

Ulrike Koehl

U Sandy Tretbar

Affiliations

Soon will be listed here.

Abstract

Engineered T cells expressing chimeric antigen receptors (CARs) have been proven as efficacious therapies against selected hematological malignancies. However, the approved CAR T cell therapeutics strictly rely on viral transduction, a time- and cost-intensive procedure with possible safety issues. Therefore, the direct transfer of transcribed CAR-mRNA into T cells is pursued as a promising strategy for CAR T cell engineering. Electroporation (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 CAR-mRNA delivery and compared with EP. LNP-CAR T cells showed a significantly prolonged efficacy in comparison with EP-CAR T cells as a result of extended CAR-mRNA persistence and CAR expression, attributed to a different delivery mechanism with less cytotoxicity and slower CAR T cell proliferation. Moreover, CAR expression and 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 underline the great potential of mRNA-LNP delivery for CAR T cell modification as next-generation transient approach for clinical studies.

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