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

Geoffrey Lynn 1, 2 Christine Sedlik 3, 4 Faezzah Baharom 1 Yaling Zhu 2 Ramiro Ramirez-Valdez 1 Vincent Coble 2 Kennedy Tobin 1 Sarah Nichols 2 Yaakov Itzkowitz 2 Neeha Zaidi 1 Joshua Gammon 5 Nicolas Blobel 1 Jordan Denizeau 3, 4 Philippe de la Rochere 3, 4 Brian Francica 6, 7 Brennan Decker 2 Mateusz Maciejewski 2 Justin Cheung 1 Hidehiro Yamane 1 Margery Smelkinson 1 Joseph Francica 1 Richard Laga 8 Joshua Bernstock 2, 9 Leonard Seymour 10 Charles Drake 6, 1 Christopher Jewell 5 Olivier Lantz 3, 4 Eliane Piaggio 3, 4 Andrew Ishizuka 1, 2 Robert Seder 1
1 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
2 Avidea Technologies, Inc
3 CIC 1428 , CBT 507 - Centre d'Investigation Clinique en Biotherapie des cancers
4 U932 - Immunité et cancer
5 University of Maryland [Baltimore]
6 The Sidney Kimmel Comprehensive Cancer Center
7 Tempest Therapeutics [San Francisco]
8 CAS - Czech Academy of Sciences [Prague]
9 BWH - Brigham & Women’s Hospital [Boston]
10 University of Oxford [Oxford]
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.
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https://www.hal.inserm.fr/inserm-02475864
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Geoffrey Lynn, Christine Sedlik, Faezzah Baharom, Yaling Zhu, Ramiro Ramirez-Valdez, et al.. Peptide–TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens. Nature Biotechnology, Nature Publishing Group, 2020, Epub ahead of print. ⟨10.1038/s41587-019-0390-x⟩. ⟨inserm-02475864⟩

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