Peptide–TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens

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. SmelkinsonJoseph 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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)320-332
Number of pages13
JournalNature biotechnology
Volume38
Issue number3
DOIs
StatePublished - Mar 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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