RNA Vaccination Drives Expansion and Brain-Licensing of T Cells to Enhance the Efficacy of Adoptive Cell Therapy in Glioblastoma

Abstract Adoptive cell therapies using chimeric antigen receptor or T cell receptor-transgenic T cells (TCR-T) are effective in treating hematological malignancies but have limited efficacy in solid tumors, particularly brain tumors. A major challenge of adoptive T cell therapy in brain tumors is lack of access to the target antigen, which is necessary for restimulation and persistence. Here, we addressed this challenge by using an mRNA vaccine encoding the cognate antigen to induce in vivo restimulation of transferred TCR-T cells in glioma models. Delivery of mRNA encoding the immunodominant MHC class I ovalbumin epitope SIINFEKL to splenic dendritic cells initiated strong expansion of adoptively transferred ovalbumin-specific OT1 CD8+ T cells to up to 80% of all circulating CD8+ T cells. RNA vaccination markedly improved T cell infiltration and retained interferon-stimulated gene signature in the brain, suppressing glioblastoma growth. The therapeutic efficacy of this approach was further demonstrated in an experimental model for a first-in-class TCR-T cell therapy targeting an HLA-A2-restricted immunodominant epitope of the human glioblastoma stemness antigen PTPRZ1. Co-administration of human dendritic cells transfected with PTPRZ1-mRNA led to rejection of orthotopically implanted primary human gliomas endogenously expressing PTPRZ1 and HLA-A2 after adoptive transfer of PTPRZ1-TCR-T cells. In summary, these findings indicate that mRNA vaccines can boost TCR-T cell therapy against glioblastoma.