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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 31.864 ) Pub Date : 2020-01-13 , DOI: 10.1038/s41587-019-0390-x
Geoffrey M. Lynn; Christine Sedlik; Faezzah Baharom; Yaling Zhu; Ramiro A. Ramirez-Valdez; Vincent L. Coble; Kennedy Tobin; Sarah R. Nichols; Yaakov Itzkowitz; Neeha Zaidi; Joshua M. Gammon; Nicolas J. Blobel; Jordan Denizeau; Philippe de la Rochere; Brian J. Francica; Brennan Decker; Mateusz Maciejewski; Justin Cheung; Hidehiro Yamane; Margery G. Smelkinson; Joseph R. Francica; Richard Laga; Joshua D. Bernstock; Leonard W. Seymour; Charles G. Drake; Christopher M. Jewell; Olivier Lantz; Eliane Piaggio; Andrew S. Ishizuka; Robert A. Seder

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:2020-01-14

 

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