Virus-like particle-mediated delivery of structure-selected neoantigens demonstrates immunogenicity and antitumoral activity in mice
Barajas Vélez, Ana (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Amengual-Rigo, Pep (Barcelona Supercomputing Center (Barcelona))
Pons-Grífols, Anna (Universitat Autònoma de Barcelona)
Ortiz, Raquel (Universitat Autònoma de Barcelona)
Gracia Carmona, Oriol (Barcelona Supercomputing Center (Barcelona))
Urrea, Víctor (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
de la Iglesia, Núria (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Blanco-Heredia, Juan (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Anjos-Souza, Carla (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Varela, Ismael (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Trinité, Benjamin (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Tarrés-Freixas, Ferran (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Rovirosa, Carla (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Lepore, Rosalba (Barcelona Supercomputing Center (Barcelona))
Vázquez, Miguel (Barcelona Supercomputing Center (Barcelona))
De Mattos-Arruda, Leticia (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Valencia, Alfonso (Barcelona Supercomputing Center (Barcelona))
Clotet Sala, Bonaventura (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Aguilar-Gurrieri, Carmen (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Guallar, Victor (Institució Catalana de Recerca i Estudis Avançats (Barcelona))
Carrillo, Jorge (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Blanco, Julià (Institut Germans Trias i Pujol)

Data:	2024
Resum:	Background: Neoantigens are patient- and tumor-specific peptides that arise from somatic mutations. They stand as promising targets for personalized therapeutic cancer vaccines. The identification process for neoantigens has evolved with the use of next-generation sequencing technologies and bioinformatic tools in tumor genomics. However, in-silico strategies for selecting immunogenic neoantigens still have very low accuracy rates, since they mainly focus on predicting peptide binding to Major Histocompatibility Complex (MHC) molecules, which is key but not the sole determinant for immunogenicity. Moreover, the therapeutic potential of neoantigen-based vaccines may be enhanced using an optimal delivery platform that elicits robust de novo immune responses. Methods: We developed a novel neoantigen selection pipeline based on existing software combined with a novel prediction method, the Neoantigen Optimization Algorithm (NOAH), which takes into account structural features of the peptide/MHC-I interaction, as well as the interaction between the peptide/MHC-I complex and the TCR, in its prediction strategy. Moreover, to maximize neoantigens' therapeutic potential, neoantigen-based vaccines should be manufactured in an optimal delivery platform that elicits robust de novo immune responses and bypasses central and peripheral tolerance. Results: We generated a highly immunogenic vaccine platform based on engineered HIV-1 Gag-based Virus-Like Particles (VLPs) expressing a high copy number of each in silico selected neoantigen. We tested different neoantigen-loaded VLPs (neoVLPs) in a B16-F10 melanoma mouse model to evaluate their capability to generate new immunogenic specificities. NeoVLPs were used in in vivo immunogenicity and tumor challenge experiments. Conclusions: Our results indicate the relevance of incorporating other immunogenic determinants beyond the binding of neoantigens to MHC-I. Thus, neoVLPs loaded with neoantigens enhancing the interaction with the TCR can promote the generation of de novo antitumor-specific immune responses, resulting in a delay in tumor growth. Vaccination with the neoVLP platform is a robust alternative to current therapeutic vaccine approaches and a promising candidate for future personalized immunotherapy.
Ajuts:	Agencia Estatal de Investigación PID2019‑106370RB‑I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2022FI_B00698
Nota:	This work was supported by the CERCA Program (2021 SGR 00452; Generalitat de Catalunya), PID2019-106370RB-I00/AEI/ https://doi.org/10.13039/501100011033 (Spanish Ministry of Science and Innovation), Grifols S. A. (Spain) and Sorigué (Spain). Funders had no role in the study design, data analysis, decision to publish, or manuscript preparation. AP-G was funded by Secretaria d'Universitats i Recerca of Generalitat de Catalunya and the European Social Fund through the fellowship 2022FI_B00698.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Journal of translational medicine, Vol. 22 Núm. 1 (december 2024) , p. 14, ISSN 1479-5876

DOI: 10.1186/s12967-023-04843-8
PMID: 38172991

14 p, 5.6 MB

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