A Dual mRNA Vaccine Against Merkel Cell Carcinoma Shows Synergy with PD-1 Blockade

Merkel cell carcinoma (MCC) is an uncommon but highly aggressive cutaneous neuroendocrine cancer, with mortality rates exceeding those of melanoma. About 80% of MCC cases in the United States are caused by the Merkel cell polyomavirus (MCPyV), which integrates into the host genome and drives tumor growth through expression of viral oncoproteins known as the large T antigen (LTA) and small T antigen.¹ Unlike most tumor-associated antigens, these viral proteins are both immunogenic and essential for tumor survival, making them ideal targets for therapeutic vaccination.

A Novel mRNA Vaccine Approach & Design

Building on advances in mRNA vaccine technology, researchers developed a novel mRNA vaccine targeting the MCPyV-LTA designed to activate strong, durable T cell–mediated immunity against MCC.² To improve the persistence of antitumor T cells—a known limitation of many cancer vaccines—the team also engineered a version of the vaccine that co-encodes interleukin-7 (IL-7), a cytokine that supports T cell proliferation and long-term immune memory.

The investigators identified a consensus sequence of the MCPyV-LTA from patient tumor samples and optimized it for translation efficiency. The mRNA was encapsulated in lipid nanoparticles (LNPs) for delivery and tested with or without a signal peptide to enhance antigen processing and dendritic cell (DC) presentation. Laboratory studies confirmed that constructs containing the signal peptide localized to the cytoplasm, improving antigen presentation while minimizing unwanted nuclear effects.

Results in Preclinical Models

To test vaccine efficacy, the researchers used a murine model in which B16 melanoma cells were engineered to express the LTA antigen (B16-LTA). Mice vaccinated intramuscularly with the LTA mRNA vaccine showed marked tumor growth suppression and improved survival compared with placebo controls. In some cases, complete tumor regression was achieved, while tumors lacking LTA expression were unaffected.

The vaccine also reprogrammed the immune environment. Draining lymph nodes showed expansion of classical dendritic cells and activated CD8⁺ T cells, while tumors displayed higher infiltration of cytotoxic lymphocytes expressing granzyme B. When combined with anti–PD-1 checkpoint blockade, the vaccine further enhanced tumor control and survival, suggesting strong synergy with existing immunotherapies.

Addressing Antigen Loss

Because antigen loss can enable tumors to evade immune attack, the authors examined residual tumors after vaccination. These tumors showed decreased LTA expression, confirming antigen loss as a resistance mechanism. However, when tumor cells with uniform, high-level LTA expression were used—mimicking the dependency seen in virus-driven human MCC—the vaccine led to complete cures, particularly when combined with PD-1 inhibition. Importantly, vaccine efficacy was maintained in aged mice, supporting relevance for older patients who represent the majority of MCC cases.

Human Relevance

To test the translational potential of their approach, the authors studied peripheral blood mononuclear cells (PBMCs) from patients with MCPyV-positive MCC. Patient cells were stimulated ex vivo using dendritic cells loaded with LTA mRNA. This vaccination strategy expanded LTA-specific CD8⁺ T cells, increased interferon-γ secretion, and enhanced killing of HLA-matched MCC tumor cells.

Single-cell RNA sequencing showed that the vaccine-induced T cells expressed genes linked to cytotoxic and proliferative activity (e.g., IFNG, PRF1, and granzyme family genes). Expanded T cell clones overlapped with previously identified virus-specific receptors, confirming that the response was antigen-directed. These findings indicate that the mRNA vaccine can effectively boost tumor-specific T cell responses in human immune cells.

Role of IL-7 in Enhancing Immunity

Further analysis of patient tumor transcriptomes revealed that higher IL7 expression was associated with increased CD8⁺ T cell infiltration and markers of “stem-like” memory T cells known to sustain long-term antitumor immunity. Building on this, the team created a dual mRNA vaccine encoding both LTA and IL-7.

In mouse models, the LTA + IL-7 vaccine produced superior tumor control, longer survival, and more robust memory T cell formation than the LTA-only vaccine. Treated mice showed greater numbers of IL-7 receptor–positive memory and effector T cells, as well as increased frequencies of antigen-specific T cells. These findings suggest that co-delivery of IL-7 enhances both the strength and durability of vaccine-induced immunity.

Clinical Implications

This study highlights 2 central principles for the next generation of cancer vaccines: targeting essential tumor antigens that cannot be lost without compromising tumor survival and incorporating immune-supportive cytokines, such as IL-7, to promote T cell longevity and memory.

These strategies address common challenges in cancer vaccine design, such as antigen variability and short-lived immune responses. Given MCC’s rising incidence and limited durable treatment options, this mRNA vaccine platform offers multiple potential applications:

• Adjuvant or neoadjuvant therapy to reduce recurrence risk after surgery.
• Combination therapy with PD-1 inhibitors for advanced or refractory MCC.
• Prophylactic use in high-risk immunosuppressed populations, such as patients with chronic lymphocytic leukemia.

References

1. Nghiem P, Bhatia S, Lipson E.J. Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma. J. Immunother. Cancer. 2021; 9, e002478.

2. Frey A, Clulo K, Fei Y, Dumit TC, Scallo F, Allen JW, Chang E, Perry CJ, Wirth LV, Jacobs D, Braun DA, Bosenberg MW, Tran TT, Clune J, Kluger HM, Olino K, Ishizuka JJ. Targeting an essential viral oncoprotein with an IL-7-enhanced mRNA vaccine induces durable immunity to Merkel cell carcinoma. Cell Rep. 2025 Oct 28;44(10):116359. doi: 10.1016/j.celrep.2025.116359. Epub 2025 Oct 1. PMID: 41042672.