Optimizing Transfection Efficiency in CAR‑T Cell Manufacturing through Multiple Administrations of Lipid-Based Nanoparticles
The existing manufacturing protocols for CAR-T cell therapies pose notable challenges, particularly in attaining a transient transfection that endures for a significant duration. To address this gap, this study aims to formulate a transfection protocol utilizing multiple lipid-based nanoparticles (L...
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Published in | ACS applied bio materials Vol. 7; no. 6; pp. 3746 - 3757 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
American Chemical Society
22.05.2024
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Abstract | The existing manufacturing protocols for CAR-T cell therapies pose notable challenges, particularly in attaining a transient transfection that endures for a significant duration. To address this gap, this study aims to formulate a transfection protocol utilizing multiple lipid-based nanoparticles (LNPs) administrations to enhance transfection efficiency (TE) to clinically relevant levels. By systematically fine-tuning and optimizing our transfection protocol through a series of iterative refinements, we have accomplished a remarkable one-order-of-magnitude augmentation in TE within the immortalized T-lymphocyte Jurkat cell line. This enhancement has been consistently observed over 2 weeks, and importantly, it has been achieved without any detrimental impact on cell viability. In the subsequent phase of our study, we aimed to optimize the gene delivery system by evaluating three lipid-based formulations tailored for DNA encapsulation using our refined protocol. These formulations encompassed two LNPs constructed from ionizable lipids and featuring systematic variations in lipid composition (iLNPs) and a cationic lipoplex (cLNP). Our findings showcased a notable standout among the three formulations, with cLNP emerging as a frontrunner for further refinement and integration into the production pipeline of CAR-T therapies. Consequently, cLNP was scrutinized for its potential to deliver CAR-encoding plasmid DNA to the HEK-293 cell line. Confocal microscopy experiments demonstrated its efficiency, revealing substantial internalization compared to iLNPs. By employing a recently developed confocal image analysis method, we substantiated that cellular entry of cLNP predominantly occurs through macropinocytosis. This mechanism leads to heightened intracellular endosomal escape and mitigates lysosomal accumulation. The successful expression of anti-CD19-CD28-CD3z, a CAR engineered to target CD19, a protein often expressed on the surface of B cells, was confirmed using a fluorescence-based assay. Overall, our results indicated the effectiveness of cLNP in gene delivery and suggested the potential of multiple administration transfection as a practical approach for refining T-cell engineering protocols in CAR therapies. Future investigations may focus on refining outcomes by adjusting transfection parameters like nucleic acid concentration, lipid-to-DNA ratio, and incubation time to achieve improved TE and increased gene expression levels. |
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AbstractList | The existing manufacturing protocols for CAR-T cell therapies pose notable challenges, particularly in attaining a transient transfection that endures for a significant duration. To address this gap, this study aims to formulate a transfection protocol utilizing multiple lipid-based nanoparticles (LNPs) administrations to enhance transfection efficiency (TE) to clinically relevant levels. By systematically fine-tuning and optimizing our transfection protocol through a series of iterative refinements, we have accomplished a remarkable one-order-of-magnitude augmentation in TE within the immortalized T-lymphocyte Jurkat cell line. This enhancement has been consistently observed over 2 weeks, and importantly, it has been achieved without any detrimental impact on cell viability. In the subsequent phase of our study, we aimed to optimize the gene delivery system by evaluating three lipid-based formulations tailored for DNA encapsulation using our refined protocol. These formulations encompassed two LNPs constructed from ionizable lipids and featuring systematic variations in lipid composition (iLNPs) and a cationic lipoplex (cLNP). Our findings showcased a notable standout among the three formulations, with cLNP emerging as a frontrunner for further refinement and integration into the production pipeline of CAR-T therapies. Consequently, cLNP was scrutinized for its potential to deliver CAR-encoding plasmid DNA to the HEK-293 cell line. Confocal microscopy experiments demonstrated its efficiency, revealing substantial internalization compared to iLNPs. By employing a recently developed confocal image analysis method, we substantiated that cellular entry of cLNP predominantly occurs through macropinocytosis. This mechanism leads to heightened intracellular endosomal escape and mitigates lysosomal accumulation. The successful expression of anti-CD19-CD28-CD3z, a CAR engineered to target CD19, a protein often expressed on the surface of B cells, was confirmed using a fluorescence-based assay. Overall, our results indicated the effectiveness of cLNP in gene delivery and suggested the potential of multiple administration transfection as a practical approach for refining T-cell engineering protocols in CAR therapies. Future investigations may focus on refining outcomes by adjusting transfection parameters like nucleic acid concentration, lipid-to-DNA ratio, and incubation time to achieve improved TE and increased gene expression levels. |
Author | Molfetta, Rosa Giulimondi, Francesca Zingoni, Alessandra Caracciolo, Giulio Amenitsch, Heinz Renzi, Serena Maiorano, Gabriele Pirrottina, Andrea Gigli, Giuseppe Palamà, Ilaria Elena Cassone, Chiara Digiacomo, Luca Pozzi, Daniela |
AuthorAffiliation | Department of Molecular Medicine CNR-NANOTEC Department of Medicine Institute of Inorganic Chemistry University of Salento Sapienza University of Rome Nanotechnology Institute |
AuthorAffiliation_xml | – name: Department of Medicine – name: University of Salento – name: Sapienza University of Rome – name: Nanotechnology Institute – name: CNR-NANOTEC – name: Institute of Inorganic Chemistry – name: Department of Molecular Medicine |
Author_xml | – sequence: 1 givenname: Francesca surname: Giulimondi fullname: Giulimondi, Francesca organization: Sapienza University of Rome – sequence: 2 givenname: Luca surname: Digiacomo fullname: Digiacomo, Luca organization: Sapienza University of Rome – sequence: 3 givenname: Serena surname: Renzi fullname: Renzi, Serena organization: Sapienza University of Rome – sequence: 4 givenname: Chiara surname: Cassone fullname: Cassone, Chiara organization: Sapienza University of Rome – sequence: 5 givenname: Andrea surname: Pirrottina fullname: Pirrottina, Andrea organization: Sapienza University of Rome – sequence: 6 givenname: Rosa surname: Molfetta fullname: Molfetta, Rosa organization: Sapienza University of Rome – sequence: 7 givenname: Ilaria Elena orcidid: 0000-0003-4420-0680 surname: Palamà fullname: Palamà, Ilaria Elena organization: CNR-NANOTEC – sequence: 8 givenname: Gabriele surname: Maiorano fullname: Maiorano, Gabriele organization: CNR-NANOTEC – sequence: 9 givenname: Giuseppe surname: Gigli fullname: Gigli, Giuseppe organization: University of Salento – sequence: 10 givenname: Heinz surname: Amenitsch fullname: Amenitsch, Heinz organization: Institute of Inorganic Chemistry – sequence: 11 givenname: Daniela surname: Pozzi fullname: Pozzi, Daniela organization: Sapienza University of Rome – sequence: 12 givenname: Alessandra surname: Zingoni fullname: Zingoni, Alessandra organization: Sapienza University of Rome – sequence: 13 givenname: Giulio orcidid: 0000-0002-8636-4475 surname: Caracciolo fullname: Caracciolo, Giulio email: giulio.caracciolo@uniroma1.it organization: Sapienza University of Rome |
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Title | Optimizing Transfection Efficiency in CAR‑T Cell Manufacturing through Multiple Administrations of Lipid-Based Nanoparticles |
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