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Dendritic cell targeting mRNA lipopolyplexes combine strong antitumor T-cell immunity with improved inflammatory safety

(2018) ACS NANO. 12(10). p.9815-9829
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Abstract
In vitro transcribed mRNA constitutes a versatile platform to encode antigens and to evoke CD8 T-cell responses. Systemic delivery of mRNA packaged into cationic liposomes (lipoplexes) has proven particularly powerful in achieving effective antitumor immunity in animal models. Yet, T-cell responses to mRNA lipoplexes critically depend on the induction of type I interferons (IFN), potent pro-inflammatory cytokines, which inflict dose-limiting toxicities. Here, we explored an advanced hybrid lipid polymer shell mRNA nanoparticle (lipopolyplex) endowed with a trimannose sugar tree as an alternative delivery vehicle for systemic mRNA vaccination. Like mRNA lipoplexes, mRNA lipopolyplexes were extremely effective in conferring antitumor T-cell immunity upon systemic administration. Conversely to mRNA lipoplexes, mRNA lipopolyplexes did not rely on type I IFN for effective T-cell immunity. This differential mode of action of mRNA lipopolyplexes enabled the incorporation of N1 methyl pseudouridine nucleoside modified mRNA to reduce inflammatory responses without hampering T-cell immunity. This feature was attributed to mRNA lipopolyplexes, as the incorporation of thus modified mRNA into lipoplexes resulted in strongly weakened T-cell immunity. Taken together, we have identified lipopolyplexes containing N1 methyl pseudouridine nucleoside modified mRNA as potent yet low-inflammatory alternatives to the mRNA lipoplexes currently explored in early phase clinical trials.
Keywords
IN-VIVO, ENHANCES TRANSLATION, CANCER-IMMUNOTHERAPY, LIPID, NANOPARTICLES, SYSTEMIC DELIVERY, PSEUDOURIDINE, MICE, ACTIVATION, EXPRESSION, MELANOMA, mRNA, lipopolyplexes, type I interferon, cancer therapy, T cell, modified nucleosides

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Citation

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Chicago
Van der Jeught, Kevin, Stefaan De Koker, Lukasz Bialkowski, Carlo Heirman, Patrick Tjok Joe, Federico Perche, Sarah Maenhout, et al. 2018. “Dendritic Cell Targeting mRNA Lipopolyplexes Combine Strong Antitumor T-cell Immunity with Improved Inflammatory Safety.” Acs Nano 12 (10): 9815–9829.
APA
Van der Jeught, K., De Koker, S., Bialkowski, L., Heirman, C., Joe, P. T., Perche, F., Maenhout, S., et al. (2018). Dendritic cell targeting mRNA lipopolyplexes combine strong antitumor T-cell immunity with improved inflammatory safety. ACS NANO, 12(10), 9815–9829.
Vancouver
1.
Van der Jeught K, De Koker S, Bialkowski L, Heirman C, Joe PT, Perche F, et al. Dendritic cell targeting mRNA lipopolyplexes combine strong antitumor T-cell immunity with improved inflammatory safety. ACS NANO. 2018;12(10):9815–29.
MLA
Van der Jeught, Kevin et al. “Dendritic Cell Targeting mRNA Lipopolyplexes Combine Strong Antitumor T-cell Immunity with Improved Inflammatory Safety.” ACS NANO 12.10 (2018): 9815–9829. Print.
@article{8600825,
  abstract     = {In vitro transcribed mRNA constitutes a versatile platform to encode antigens and to evoke CD8 T-cell responses. Systemic delivery of mRNA packaged into cationic liposomes (lipoplexes) has proven particularly powerful in achieving effective antitumor immunity in animal models. Yet, T-cell responses to mRNA lipoplexes critically depend on the induction of type I interferons (IFN), potent pro-inflammatory cytokines, which inflict dose-limiting toxicities. Here, we explored an advanced hybrid lipid polymer shell mRNA nanoparticle (lipopolyplex) endowed with a trimannose sugar tree as an alternative delivery vehicle for systemic mRNA vaccination. Like mRNA lipoplexes, mRNA lipopolyplexes were extremely effective in conferring antitumor T-cell immunity upon systemic administration. Conversely to mRNA lipoplexes, mRNA lipopolyplexes did not rely on type I IFN for effective T-cell immunity. This differential mode of action of mRNA lipopolyplexes enabled the incorporation of N1 methyl pseudouridine nucleoside modified mRNA to reduce inflammatory responses without hampering T-cell immunity. This feature was attributed to mRNA lipopolyplexes, as the incorporation of thus modified mRNA into lipoplexes resulted in strongly weakened T-cell immunity. Taken together, we have identified lipopolyplexes containing N1 methyl pseudouridine nucleoside modified mRNA as potent yet low-inflammatory alternatives to the mRNA lipoplexes currently explored in early phase clinical trials.},
  author       = {Van der Jeught, Kevin and De Koker, Stefaan and Bialkowski, Lukasz and Heirman, Carlo and Joe, Patrick Tjok and Perche, Federico and Maenhout, Sarah and Bevers, Sanne and Broos, Katrijn and Deswarte, Kim and Malard, Virginie and Hammad, Hamida and Baril, Patrick and Benvegnu, Thierry and Jaffres, Paul-Alain and Kooijmans, Sander AA and Schiffelers, Raymond and Lienenklaus, Stefan and Midoux, Patrick and Pichon, Chantal and Breckpot, Karine and Thielemans, Kris},
  issn         = {1936-0851},
  journal      = {ACS NANO},
  language     = {eng},
  number       = {10},
  pages        = {9815--9829},
  title        = {Dendritic cell targeting mRNA lipopolyplexes combine strong antitumor T-cell immunity with improved inflammatory safety},
  url          = {http://dx.doi.org/10.1021/acsnano.8b00966},
  volume       = {12},
  year         = {2018},
}

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