MSC-delivered high-affinity variants of soluble PD1 lead to tumor regression.

BACKGROUND AIMS: Immune checkpoint therapies aim to restore anti-tumor immunity by blocking inhibitory signals that suppress T-cell activation. The most effective current strategies use humanized antibodies targeting PD1 or its ligand PDL1. However, due to their large size, antibodies often exhibit limited tissue diffusion, resulting in poor penetration into solid tumors. METHODS: To address this challenge, we developed a novel checkpoint inhibitor approach that uses mesenchymal stromal cells (MSCs) to deliver a high-affinity, soluble PD1 receptor (sPD1-HAC). RESULTS: We found that sPD1-HAC produced as an IgG1-Fc fusion protein provided functional expression in MSCs. The sPD1-HAC-IgG1-Fc fusion protein (sPD1HAC) showed strong and specific binding to PDL1 and could outcompete recombinant PD1 and anti-PDL1 antibodies, including the clinically approved durvalumab. Although the sPD1HAC variant was designed to block human PD1-PDL1 signaling, it also bound murine PDL1 and blocked the binding of mouse-specific PDL1 antibodies. Accordingly, we found significant anti-tumor activity of intravenously administered MSC.sPD1HAC in an aggressive B16-F10 cancer model. CONCLUSIONS: This cell-based immune checkpoint approach offers a potential therapeutic option for targeting stroma-rich, hard-to-treat tumors.