A first-in-class Erythrocyte-anti-PD-1 conjugate overcomes immunotherapy resistance across pan-solid tumors: A phase I trial

Background: Despite the success of immune checkpoint blockade (ICB), most patients fail to respond or eventually develop resistance due to insufficient efficacy or immune-related toxicities. We developed alphaPD-1-Ery, an erythrocyte-PD-1 antibody conjugate in which anti-PD-1 antibodies are covalently linked to erythrocyte membranes. Unlike conventional antibodies, alphaPD-1-Ery selectively accumulates in the spleen, where it efficiently engages and activates T cells, leading to reductions in immunosuppressive myeloid cells. These coordinated effects remodel the immune landscape, reprogram the tumor microenvironment, and suppress tumor growth in ICB-resistant models. Based on these findings, we initiated a phase I investigator-initiated trial of alphaPD-1-Ery in patients with advanced solid tumors that had progressed on prior PD-1/PD-L1 therapy (NCT06026605). Methods: This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of alphaPD-1-Ery monotherapy. Eligible patients had histologically confirmed solid tumors progressing on prior PD-1/PD-L1-containing regimens. alphaPD-1-Ery was administered intravenously every 21 days at dose levels of 2×10¹¹ or 3×10¹¹ cells per infusion. Safety was assessed per NCI-CTCAE v5.0, and efficacy per RECIST v1.1. Results: As of October 31, 2025, 14 heavily pretreated patients with 11 tumor types were enrolled. No dose-limiting toxicities or TRAEs > grade 3 occurred, and no severe immunotoxicities were observed. alphaPD-1-Ery showed encouraging anti-tumor activity, with a DCR of 78.6% (11/14) and an ORR of 42.9% (6/14), including 1 CR and 5 PRs. Responses were more pronounced at the higher dose level (ORR 57.1%, 4/7), supporting a dose-dependent effect. Median PFS was 5.5 months, and the 12-month OS rate was 71.4%, indicating durable benefit. PK analysis demonstrated dose-proportional exposure, with mean Cmax values of 2,711 and 5,107 cells/µL for the low and high doses, respectively. Tmax ranged from 0.5 to 48 hours, and engineered erythrocytes persisted for 7-21 days. Free antibody levels remained <5%, confirming in-vivo stability and spleen-targeted delivery. Biomarker analysis identified a spleen-associated myeloid signature: responders had higher baseline circulating PMN-MDSCs and showed rapid post-treatment declines compared with non-responders, consistent with spleen-mediated myeloid modulation. Conclusion: alphaPD-1-Ery is safe, well tolerated, and demonstrates encouraging anti-tumor activity in ICB-resistant solid tumors. Erythrocyte-drug conjugates represent a novel therapeutic class for overcoming resistance to checkpoint blockade, with broad implications for cancer treatment and drug development.