Small circular RNA (circRNA) vaccines consisting of a short IRES site, a Kozak sequence, and optimized codons for one or more antigen epitopes developed by Zang and Liu et al. demonstrated high stability and sustained antigen translation for at least 7 days. Ionizable lipid nanoparticles (LNPs) delivered circRNA to intranodal APCs, and led to DC maturation and RIG-I activation, but low protein kinase R activation. In young and 1-year-old mice, circRNA was well tolerated and elicited robust and durable T cell responses, remodeled the TME, and, when combined with checkpoint blockade (ICB), inhibited poorly immunogenic or ICB-resistant tumors.
Contributed by Ute Burkhardt
ABSTRACT: Messenger RNA vaccines have shown strong prophylactic efficacy against viral infections. Here we show that antigen-encoding small circular RNAs (circRNAs) loaded in lipid nanoparticles elicit potent and durable T cell responses for robust tumour immunotherapy after subcutaneous injection in mice, particularly when combined with immune checkpoint inhibition. The small circRNA vaccines are highly stable and show low levels of activation of protein kinase R as well as low cytotoxicity, enabling long-lasting antigen translation (longer than 1 week in cells). Relative to large protein-encoding unmodified or modified mRNAs and circRNAs, small circRNA vaccines elicited up to 10-fold antigen-specific T cells in mice and accounted for 30-75% of the total peripheral CD8(+) T cells over 6 months. Small circRNA vaccines encoding tumour-associated antigens, neoantigens and oncoviral or viral antigens elicited substantial CD8(+) and CD4(+) T cell responses in young adult mice and in immunosenescent aged mice. Combined with immune checkpoint inhibition, monovalent and multivalent circRNA vaccines reduced tumour-induced immunosuppression and inhibited poorly immunogenic mouse tumours, including melanoma resistant to immune checkpoint blockade.
Author Info: (1) Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, H
Author Info: (1) Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China. (2) Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. (3) The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China. (4) Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. (5) Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. (6) Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. (7) Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. (8) College of Biological Science and Medical Engineering, Donghua University, Shanghai, China. (9) Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. (10) Department of Biostatistics, School of Medicine; Bioinformatics Shared Resource, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. (11) Department of Biostatistics, School of Medicine; Bioinformatics Shared Resource, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. (12) Genomics Core, Virginia Commonwealth University, Richmond, VA, USA. (13) Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA. (14) Department of Human and Molecular Genetics and Institute of Molecular Medicine, School of Medicine; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. (15) Department of Biostatistics, School of Medicine; Bioinformatics Shared Resource, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. (16) Department of Biostatistics, School of Medicine; Bioinformatics Shared Resource, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. (17) Department of Human and Molecular Genetics and Institute of Molecular Medicine, School of Medicine; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. (18) Department of Biostatistics, School of Medicine; Bioinformatics Shared Resource, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. (19) Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. guizhiz@med.umich.edu. Bioinnovations in Brain Cancer, Biointerfaces Institute; The Developmental Therapeutics Program, Rogel Cancer Center; Center for RNA Biomedicine; MI-AORTA program, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, USA. guizhiz@med.umich.edu.
