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

TL;DR

A new mRNA vaccine targeting a key protein in Merkel cell carcinoma improves immune response and tumor control by combining the antigen with IL-7.

Contribution

The study introduces an IL-7-enhanced mRNA vaccine targeting an essential viral oncoprotein to overcome antigen loss and improve T cell durability.

Findings

Antigen loss rapidly causes resistance when non-essential antigens are targeted in mouse models.

Co-encoding LTA and IL-7 enhances T cell expansion, memory differentiation, and tumor control.

The vaccine's design may improve the efficacy of mRNA therapeutics by co-encoding memory signals with antigens.

Abstract

Although mRNA technologies have reinvigorated cancer vaccine development, the identification of strong antigens with consistent tumor cell expression and generation of durable antigen-specific CD8+ T cell memory remain key challenges. We identified the Merkel cell carcinoma (MCC) large T antigen (LTA) as an optimal vaccine target, essential for tumor cell survival and immunogenic in a cancer with high unmet clinical need. We developed an mRNA vaccine to MCC-LTA in murine studies and patient samples. We showed that antigen loss develops rapidly and causes resistance in mouse models when immunogenic, but non-essential antigens are targeted. To improve T cell response 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 improved antigen-specific T cell expansion, memory differentiation, and tumor control. We propose that the principles of antigen essentiality and memory signal co-encoding may be adapted to improve the efficacy of mRNA therapeutics.

Frey et al. develop an mRNA immunotherapy for Merkel cell carcinoma, a lethal neuroendocrine skin cancer with high unmet medical need. They target an essential viral oncoprotein with an IL-7-enhanced vaccine, overcoming two central challenges in the development of therapeutic cancer vaccines: antigen loss and CD8+ T cell response durability.

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