mRNA-based immunotherapy platform targeting endometrial cancer

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Abstract Background Conventional therapies for endometrial cancer (EC), one of the most prevalent gynecological malignancies, remain inefficient, particularly in advanced stages and relapse with chemoresistant disease, underscoring the urgent need for new therapeutic strategies. Here, we present an approach and key considerations for developing a safe ex vivo mRNA-based vaccine potentially targeting EC. Methods Based on expression analysis in patient-derived endometrial tumor tissues, we identify two potential targets – fibroblast activation protein (FAP) and melanoma-associated antigen A4 (MAGEA4) – for immunotherapy using an ex vivo vaccine setting. We optimized the individual components of the mRNA expression cassette to enhance translation fidelity and antigen expression. Results We selected an optimal 5′ untranslated region (UTR) and fine-tuned the translation termination signal to prevent readthrough and generation of unintended neoantigens. Functionally, the ex vivo mRNA vaccine elicited a robust T cell response, particularly when combining both FAP and MAGEA4 antigens. MAGEA4 expression correlated with disease severity in EC tumor tissue, reinforcing its relevance as both a prognostic marker and immunotherapeutic target. Its combination with FAP, expressed by both EC cells and cancer-associated fibroblasts, as part of the tumor microenvironment, may facilitate immune evasion and promote tumor infiltration. Conclusions Our data provides evidence that FAP and MAGEA4 antigens delivered via mRNA can drive effective T cell activation. This proof-of-concept study establishes a framework for developing immune-based interventions and more effective treatment strategies for patients with EC.

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