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Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells.

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Title: Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells.
Authors: Le Moignic, A.1,2, Malard, V.3, Benvegnu, T.4, Lemiègre, L.4, Berchel, M.5, Jaffrès, P.-A.5, Baillou, C.1,2, Delost, M.2, Macedo, R.2, Rochefort, J.2,6, Lescaille, G.2,6, Pichon, C.3, Lemoine, F.M.1,2,7 francois.lemoine@sorbonne-universite.fr, Midoux, P.3 patrick.midoux@cnrs.fr, Mateo, V.1,2
Source: Journal of Controlled Release. May2018, Vol. 278, p110-121. 12p.
Subjects: Messenger RNA, Cancer vaccines, Dendritic cells, Drug delivery devices, Clinical trials
Abstract: Clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Their proper delivery to dendritic cells (DCs) requires their protection against RNase degradation and more specificity for dose reduction. Lipid-Polymer-RNA lipopolyplexes (LPR) are attractive mRNA delivery systems and their equipment with mannose containing glycolipid, specific of endocytic receptors present on the membrane of DCs is a valuable strategy. In this present work, we evaluated the capacity of LPR functionalized with a tri-antenna of α- d -mannopyranoside (triMN-LPR) concerning (i) their binding to CD209/DC-SIGN and CD207/Langerin expressing cell lines, human and mouse DCs and other hematopoietic cell populations, (ii) the nature of induced immune response after in vivo immunization and (iii) their therapeutic anti-cancer vaccine efficiency. We demonstrated that triMN-LPR provided high induction of a local inflammatory response two days after intradermal injection to C57BL/6 mice, followed by the recruitment and activation of DCs in the corresponding draining lymph nodes. This was associated with skin production of CCR7 and CXCR4 at vaccination sites driving DC migration. High number of E7-specific T cells was detected after E7-encoded mRNA triMN-LPR vaccination. When evaluated in three therapeutic pre-clinical murine tumor models such as E7-expressing TC1 cells, OVA-expressing EG7 cells and MART-1-expressing B16F0 cells, triMN-LPR carrying mRNA encoding the respective antigens significantly exert curative responses in mice vaccinated seven days after initial tumor inoculation. These results provide evidence that triMN-LPR give rise to an efficient stimulatory immune response allowing for therapeutic anti-cancer vaccination in mice. This mRNA formulation should be considered for anti-cancer vaccination in Humans. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Controlled Release is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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DbLabel: Engineering Source
An: 129486377
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PubTypeId: academicJournal
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  Data: Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells.
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  Data: <searchLink fieldCode="AR" term="%22Le+Moignic%2C+A%2E%22">Le Moignic, A.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Malard%2C+V%2E%22">Malard, V.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Benvegnu%2C+T%2E%22">Benvegnu, T.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Lemiègre%2C+L%2E%22">Lemiègre, L.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Berchel%2C+M%2E%22">Berchel, M.</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Jaffrès%2C+P%2E-A%2E%22">Jaffrès, P.-A.</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Baillou%2C+C%2E%22">Baillou, C.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Delost%2C+M%2E%22">Delost, M.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Macedo%2C+R%2E%22">Macedo, R.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Rochefort%2C+J%2E%22">Rochefort, J.</searchLink><relatesTo>2,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Lescaille%2C+G%2E%22">Lescaille, G.</searchLink><relatesTo>2,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Pichon%2C+C%2E%22">Pichon, C.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Lemoine%2C+F%2EM%2E%22">Lemoine, F.M.</searchLink><relatesTo>1,2,7</relatesTo><i> francois.lemoine@sorbonne-universite.fr</i><br /><searchLink fieldCode="AR" term="%22Midoux%2C+P%2E%22">Midoux, P.</searchLink><relatesTo>3</relatesTo><i> patrick.midoux@cnrs.fr</i><br /><searchLink fieldCode="AR" term="%22Mateo%2C+V%2E%22">Mateo, V.</searchLink><relatesTo>1,2</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Controlled+Release%22">Journal of Controlled Release</searchLink>. May2018, Vol. 278, p110-121. 12p.
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  Data: Clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Their proper delivery to dendritic cells (DCs) requires their protection against RNase degradation and more specificity for dose reduction. Lipid-Polymer-RNA lipopolyplexes (LPR) are attractive mRNA delivery systems and their equipment with mannose containing glycolipid, specific of endocytic receptors present on the membrane of DCs is a valuable strategy. In this present work, we evaluated the capacity of LPR functionalized with a tri-antenna of α- d -mannopyranoside (triMN-LPR) concerning (i) their binding to CD209/DC-SIGN and CD207/Langerin expressing cell lines, human and mouse DCs and other hematopoietic cell populations, (ii) the nature of induced immune response after in vivo immunization and (iii) their therapeutic anti-cancer vaccine efficiency. We demonstrated that triMN-LPR provided high induction of a local inflammatory response two days after intradermal injection to C57BL/6 mice, followed by the recruitment and activation of DCs in the corresponding draining lymph nodes. This was associated with skin production of CCR7 and CXCR4 at vaccination sites driving DC migration. High number of E7-specific T cells was detected after E7-encoded mRNA triMN-LPR vaccination. When evaluated in three therapeutic pre-clinical murine tumor models such as E7-expressing TC1 cells, OVA-expressing EG7 cells and MART-1-expressing B16F0 cells, triMN-LPR carrying mRNA encoding the respective antigens significantly exert curative responses in mice vaccinated seven days after initial tumor inoculation. These results provide evidence that triMN-LPR give rise to an efficient stimulatory immune response allowing for therapeutic anti-cancer vaccination in mice. This mRNA formulation should be considered for anti-cancer vaccination in Humans. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Journal of Controlled Release is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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