Targeting an essential viral oncoprotein with an IL-7-enhanced mRNA vaccine induces durable immunity to Merkel cell carcinoma

mRNA technologies have reinvigorated cancer vaccine development, but the optimal antigenic targets remain unclear. Further, generation of memory CD8+ T cell responses, critical for durable immunity, remains a challenge. We identified the Merkel cell carcinoma (MCC) Large T Antigen (LTA) as an exemplar target antigen, required for tumor cell survival and immunogenic in a cancer with rising incidence and high unmet need. We developed an mRNA vaccine to MCC-LTA in murine studies and MCC patient samples and showed that antigen loss developed rapidly and caused resistance when the antigen was not essential for tumor survival. To improve T cell response quality and durability, we co-encoded LTA and IL-7, co-localizing proliferative and memory signals spatially and temporally with antigen exposure. IL-7-containing mRNA vaccines enhanced T cell expansion, memory differentiation and sustained tumor control. We propose that antigen essentiality and signal co-encoding may be adapted to improve the efficacy of mRNA therapeutics. Overall design: scRNAseq, CITE-seq, TCRseq; MCC patient T cells were cultured in IL-2+IL-7 for 25 days. Every 7 days they were stimulated with monocyte-derived DCs either expressing the LTA vaccine or with placebo lipid nanoparticles. On the day prior to sequencing, T cells were stimulated with either placebo DCs, LTA-DCs or matched primary tumor cells prior to sequencing using the 5' 10x Genomics platform. Cell hashing / HTOs were used to distinguish experimental conditions.