Lipo-based nanoparticles (LNPs) containing mRNA efficiently elicit immune responses, possess adjuvant activity, and induce in situ antigen expression. Bevers et al. optimized the molar ratio and composition of the 4 LNP components (ionizable lipid, phospholipid, cholesterol, and PEGylated lipid) for elicitation of CD8+ T cell responses following i.v. administration of an mRNA vaccine encoding the E7 oncoprotein. The optimized mRNA-LNP increased transfection and activation of splenic immune cells (in mice and non-human primates), and elicited strong antitumor responses (in a TC-1 mouse model). CD8+ T cell responses depended on IFNAR signaling, phagocytes, and B cells.
Contributed by Margot O’Toole
ABSTRACT: mRNA vaccines have recently proven to be highly effective against SARS-CoV-2. Key to their success is the lipid-based nanoparticle (LNP), which enables efficient mRNA expression and endows the vaccine with adjuvant properties that drive potent antibody responses. Effective cancer vaccines require long-lived, qualitative CD8 T cell responses instead of antibody responses. Systemic vaccination appears to be the most effective route, but necessitates adaptation of LNP composition to deliver mRNA to antigen presenting cells. Using a design-of-experiments methodology, we tailored mRNA-LNP compositions to achieve high magnitude tumor-specific CD8 T cell responses within a single round of optimization. Optimized LNP compositions resulted in enhanced mRNA uptake by multiple splenic immune cell populations. Type I interferon and phagocytes were found essential for the T cell response. Surprisingly, we also discovered a yet unidentified role of B cells in stimulating the vaccine-elicited CD8 T cell response. Optimized LNPs displayed a similar, spleen-centered biodistribution profile in non-human primates and did not trigger histopathological changes in liver and spleen, warranting their further assessment in clinical studies. Taken together, our study clarifies the relationship between nanoparticle composition and their T cell stimulatory capacity and provides novel insights into the underlying mechanisms of effective mRNA-LNP based antitumor immunotherapy.