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Peptide–TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens
Nature Biotechnology ( IF 46.9 ) Pub Date : 2020-01-13 , DOI: 10.1038/s41587-019-0390-x
Geoffrey M Lynn 1, 2 , Christine Sedlik 3, 4 , Faezzah Baharom 1 , Yaling Zhu 2 , Ramiro A Ramirez-Valdez 1 , Vincent L Coble 2 , Kennedy Tobin 1 , Sarah R Nichols 2 , Yaakov Itzkowitz 2 , Neeha Zaidi 1 , Joshua M Gammon 5 , Nicolas J Blobel 1 , Jordan Denizeau 3, 4 , Philippe de la Rochere 3, 4 , Brian J Francica 6, 7 , Brennan Decker 2 , Mateusz Maciejewski 2 , Justin Cheung 1 , Hidehiro Yamane 1 , Margery G Smelkinson 8 , Joseph R Francica 1 , Richard Laga 9 , Joshua D Bernstock 2, 10 , Leonard W Seymour 11 , Charles G Drake 6, 12 , Christopher M Jewell 5 , Olivier Lantz 3, 4 , Eliane Piaggio 3, 4 , Andrew S Ishizuka 1, 2 , Robert A Seder 1
Affiliation  

Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide–TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.

更新日期:2020-01-13
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