Journal Article

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

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

2020

Overview

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. Cancer vaccines that self-assemble into uniform nanoparticles improve tumor clearance.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/590/1962 / 631/250/590/2030 / 631/67/1059/2325 / 631/67/580 / Adjuvants / Adjuvants, Immunologic - chemistry / Agriculture / Animal models / Animals / Antigen (tumor-associated) / Antigen-presenting cells / Antigens / Antigens, Neoplasm - immunology / Bioinformatics / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Cancer / Cancer vaccines / Cancer Vaccines - administration & dosage / Cancer Vaccines - immunology / Care and treatment / CD8 antigen / CD8-Positive T-Lymphocytes - metabolism / Cell activation / Cell culture / Cell Line, Tumor / Conjugate vaccines / Conjugates / Customization / Health aspects / Immunity / Immunology / Life Sciences / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Melanoma, Experimental - drug therapy / Melanoma, Experimental - immunology / Mice / Nanoparticles / Neoantigens / Peptides / Physiological aspects / Precision Medicine / Primates / Product development / Self-assembly / Single-nucleotide polymorphism / T cells / Toll-Like Receptor 7 - immunology / Toll-Like Receptor 8 - immunology / Tumors / Vaccination / Vaccines / Vaccines, Conjugate