mRNA-based immunotherapy improves the efficacy of adoptively transferred TCR transgenic T cells in a murine solid...

Adoptive T cell therapy (ACT) has shown remarkable clinical success in treating haematological malignancies; however, its efficacy against solid tumours remains limited. This is largely due to poor persistence and functionality of transferred T cells, restricted tumour infiltration, and the presence of an immunosuppressive tumour microenvironment. Here, using the MC38-OVA murine tumour model, we tested whether combining Transgenic T cell receptor (TCR^tg) T cell therapy with an adjunctive mRNA-based immunotherapy could address these challenges and drive effective and long-lasting anti-tumour response. Tumour-bearing mice were treated with different numbers of in vivo-activated, ovalbumin (OVA)-specific TCR^tg CD8⁺ T cells harvested from OT-I mice, either alone or in combination with lipid nanoparticle (LNP)-encapsulated mRNA encoding OVA. Tumour progression was monitored, and analyses were performed to assess survival, T cell expansion, phenotype, infiltration, and effector function. The combination therapy of a low dose of TCR^tg T cells and mRNA immunotherapy led to robust and durable anti-tumour responses, significantly improving survival compared to monotherapies. Notably, transferred TCR^tg T cells expanded only following mRNA immunotherapy, and circulating TCR^tg T cells exhibited a memory precursor and effector memory phenotype. These cells infiltrated tumours effectively and displayed more potent cytotoxic activity, resulting in regression of large tumours-even without prior lymphodepletion. Overall, our findings demonstrate that mRNA immunotherapy can substantially enhance the efficacy of TCR^tg T cell therapy in a solid tumour model. This combinatorial approach holds promise for overcoming key limitations of ACT by boosting T cell expansion, persistence, infiltration, and functional capacity within the tumour microenvironment.