Erythrocyte-anti-PD1 conjugates for advanced solid tumors resistant to anti-PD1/PDL1: preclinical characterization and a phase 1 trial

Despite the clinical success of immune checkpoint blockade therapy, most patients do not benefit because of inadequate efficacy, resistance, and/or toxicities. Researchers at Westlake University (Hangzhou, China) developed an erythrocyte-antibody conjugate in which anti-PD1 antibodies are covalently linked to erythrocyte membranes (αPD1-Ery). Accumulating in the spleen, αPD1-Ery remodels the immune landscape by expanding effector T cells and reducing immunosuppressive myeloid cells. These changes suppress tumor growth in syngeneic mouse models. A first-in-human phase 1 trial enrolled 14 patients with advanced cancers resistant to prior anti-PD1/PDL1 therapy. Patients received αPD1-Ery at 2 x 10¹¹ or 3 x 10¹¹ cells. Repeated administration resulted in no dose-limiting toxicities or treatment-related adverse events grade > 3. The objective response rate was 42.9% (1 complete and 5 partial responses) and the disease control rate was 78.6%. Notably, αPD1-Ery rapidly reduced circulating immunosuppressive myeloid cells. The authors conclude that these findings support spleen-targeted PD1 blockade by erythrocyte-antibody conjugates as a potential strategy for cancer immunotherapy.