迈向个性化癌症疫苗:LNP介导的多表位mRNA递送可延长侵袭性黑色素瘤模型的生存期

Personalized cancer vaccines (PCVs) open new doors for immunotherapy by harnessing the immune system to target tumor specific neoantigens ― mutated proteins ― unique to an individual's cancer. Lipid nanoparticle (LNP)-based mRNA vaccines, shown to be effective against COVID-19, serve as a suitable platform for delivering multi-epitope neoantigen mRNA payloads. LNP drug product for PCV applications however, may require optimization of the multi-antigenic mRNA cargo, target tissue uptake, and endosomal release, along with frequent therapeutic dosing. We identified 10 melanoma-specific antigens and synthesized multiple multi-antigen mRNA constructs encoding various antigen combinations, with and without marker epitopes such as ovalbumin (OVA), eGFP, and firefly luciferase (Fluc). We developed proprietary ionizable lipids and encapsulated the various multi-epitope mRNA constructs in LNPs and evaluated their performance in well-established in vitro cell based assays and a B16F10 syngeneic mouse melanoma model. The in vitro cell-based assays confirmed effective LNP-mediated delivery, mRNA translation, and antigen presentation via major histocompatibility complex (MHC) molecules. In vivo imaging demonstrated payload expression 6 hours post-injection. Selected multi-epitope mRNA-LNP formulations were administered intramuscularly in B16F10 tumor-bearing mice. Multi-epitope comprising LNPs significantly reduced mean tumor growth rate and extended survival in vaccinated mice compared to controls. Additionally, repeated dosing regimens showed favorable safety profiles. These results demonstrate that our proprietary LNP platform efficiently delivers multi-epitope mRNA LNPs, eliciting potent anti-tumor immune responses in a relevant melanoma model and demonstrating safety of repeated LNP administrations for shared or individualized cancer vaccine applications. This positions our LNP as a promising candidate for further developing PCVs and accelerating new personalized medicine to clinic.