An anti-cancer cell therapy platform utilizing ex vivo physiologic dendritic cells expressing mRNA-encoded antigens and immune checkpoint blockers

Therapeutic vaccines have struggled to effectively combat cancer. The core challenge lies in generating a durable and diverse immune response capable of eradicating tumors. The limited clinical success of therapeutic vaccination attempts highlights the need for new strategies that combine robust T cell memory induction with immune checkpoint blockade (ICB) delivery at the antigen presenting cell (APC)-T cell interface. To address this, we utilized "physiologically induced dendritic cells (phDCs)," a clinically validated APC phenotype generated via platelet P-selectin engagement of monocyte PSGL-1. Human and murine phDCs were transfected ex vivo using lipid nanoparticle (LNP) formulations with mRNA encoding antigens and cell-surface-anchored ICB antibodies, creating “armored” phDCs. Intravenous administration of these phDCs stimulated antigen-specific T cells, suppressed tumors, and generated long-term immune memory in murine cancer models. Moreover, in an autoimmune NOD model, where anti-PD1 accelerates type-1 diabetes, serial systemic treatments with anti-PD1 "armored" phDCs failed to induce disease onset. These findings demonstrate the potential of mRNA “armored” phDCs to drive anti-tumor efficacy via potent stimulation of immune responses and deliver of ICB antibodies with significantly reduced immunotoxicity.