Virus-like particle-mediated delivery of structure-selected neoantigens demonstrates immunogenicity and antitumoral activity in mice
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Published:2024-01-03
Issue:1
Volume:22
Page:
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ISSN:1479-5876
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Container-title:Journal of Translational Medicine
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language:en
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Short-container-title:J Transl Med
Author:
Barajas Ana, Amengual-Rigo Pep, Pons-Grífols Anna, Ortiz Raquel, Gracia Carmona Oriol, Urrea Victor, de la Iglesia Nuria, Blanco-Heredia Juan, Anjos-Souza Carla, Varela Ismael, Trinité Benjamin, Tarrés-Freixas Ferran, Rovirosa Carla, Lepore Rosalba, Vázquez Miguel, de Mattos-Arruda Leticia, Valencia Alfonso, Clotet Bonaventura, Aguilar-Gurrieri CarmenORCID, Guallar Victor, Carrillo Jorge, Blanco Julià
Abstract
Abstract
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.
Funder
Departament de Salut, Generalitat de Catalunya Ministerio de Ciencia e Innovación Secretaria d'Universitats i Recerca - Generalitat de Catalunya Grifols Sorigué
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine
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