Lynn and Sedlik et al. developed a vaccine platform in which charge-modified neoantigens conjugated to polymer-coupled TLR-7/8a adjuvant self-assembled into particles of a uniform size. This system allowed for precise loading of diverse peptides and improved neoantigen uptake and presentation by APCs. In mice, vaccine delivery induced CD8+ T cell responses against a higher proportion of predicted neoantigens than other delivery methods, and validated prediction tools. Delivery of immunogenic neoantigens induced antitumor efficacy in several mouse models. Neoantigen-specific CD8+ and CD4+ T cell responses were also seen in non-human primates.
Contributed by Lauren Hitchings
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.
Author Info: (1) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. geoffrey.lynn@avideatechno
Author Info: (1) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. geoffrey.lynn@avideatechnologies.com. Avidea Technologies, Inc, Baltimore, MD, USA. geoffrey.lynn@avideatechnologies.com. (2) Institut Curie, PSL Research University, Paris, France. Centre d'Investigation Clinique Biotherapie, Institut Curie, Paris, France. (3) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. (4) Avidea Technologies, Inc, Baltimore, MD, USA. (5) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. (6) Avidea Technologies, Inc, Baltimore, MD, USA. (7) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. (8) Avidea Technologies, Inc, Baltimore, MD, USA. (9) Avidea Technologies, Inc, Baltimore, MD, USA. (10) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. (11) Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA. (12) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. (13) Institut Curie, PSL Research University, Paris, France. Centre d'Investigation Clinique Biotherapie, Institut Curie, Paris, France. (14) Institut Curie, PSL Research University, Paris, France. Centre d'Investigation Clinique Biotherapie, Institut Curie, Paris, France. (15) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Tempest Therapeutics, San Francisco, CA, USA. (16) Avidea Technologies, Inc, Baltimore, MD, USA. (17) Avidea Technologies, Inc, Baltimore, MD, USA. (18) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. (19) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. (20) Biological Imaging Section, Research Technologies Branch, NIAID, NIH, Bethesda, MD, USA. (21) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. (22) Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic. (23) Avidea Technologies, Inc, Baltimore, MD, USA. Department of Neurosurgery, Brigham and Women's Hospital, Harvard University, Boston, MA, USA. (24) Department of Oncology, University of Oxford, Oxford, UK. (25) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA. (26) Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA. (27) Institut Curie, PSL Research University, Paris, France. Centre d'Investigation Clinique Biotherapie, Institut Curie, Paris, France. (28) Institut Curie, PSL Research University, Paris, France. Centre d'Investigation Clinique Biotherapie, Institut Curie, Paris, France. (29) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. Avidea Technologies, Inc, Baltimore, MD, USA. (30) Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. rseder@mail.nih.gov.
