Talk abstracts
Talk on Saturday 09:15-09:30am submitted by Xiang Liu
Small Circular mRNA Vaccines for Tumor Immunotherapy
Xiang Liu (Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan.), Yu Zhang (The Institute of Basic Medicine and Cancer, Chinese Academy of Sciences), Guizhi Zhu (Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan.)
Abstract:
Messenger RNA (mRNA) has emerged as a novel vaccine platform and has proven highly effective during pandemic. This platform had also found application in the development of cancer vaccines.
Despite the encouraging outcomes observed in early-phase clinical trials, there are still certain concerns associated with current mRNA-based cancer vaccines such as limited stability, suboptimal tumor therapy potency and durability, and limited safety. Here, we report novel highly stable antigen-encoding small circular mRNA (circRNA) vaccines that elicit potent and durable T cell responses for robust tumour immunotherapy. Compared to modified mRNA and current long circRNA, small circRNA shows superior stability, minimal protein kinase R activation, and low cytotoxicity. This allows small circRNA vaccines to sustain efficient antigen translation over an extended period, while activating pattern recognition receptors for innate immunostimulation. Relative to several modified mRNAs, nanocarrier-delivered small circRNA vaccines show superior safety and elicit up to 10-fold antigen-specific T cells, accounting for ~25%-75% total peripheral CD8+ T cells over 6 months in mice. circRNA vaccines are applicable for various major histocompatibility complex I/II-restricted tumour and viral (neo)antigens to elicit CD8+ and CD4+ T cell responses, in young adult and immunosenescent aged mice. In mice, mono-/multi-valent circRNA vaccines plus immune checkpoint blockade reduced tumour immunosuppression and eradicated multiple types of tumours, including immunotherapy-resistant BrafV600E melanoma. Overall, small circRNA vaccines represent a promising advancement in the field of tumor immunotherapy, offering optimal stability, safety, and the potential to generate potent and enduring immune responses against a variety of tumors.
Keywords: Circular mRNA, Cancer immunotherapy