Erythrocyte–anti–PD-1 conjugates in patients with advanced solid tumors resistant to anti–PD-1/PD-L1 therapy: Long-term follow-up of a phase I trial.

Abstract

2553 Background: Despite the clinical success of immune checkpoint blockade, most patients with advanced solid tumors fail to achieve durable benefit due to limited efficacy and/or immune-related toxicities. αPD-1-Ery is an erythrocyte–antibody conjugate that covalently links an anti–PD-1 antibody to erythrocyte membranes. Unlike conventional antibodies, αPD-1-Ery preferentially accumulates in the spleen, where it remodels the splenic immune microenvironment by expanding effector T cells and reducing immunosuppressive myeloid cell reservoirs, thereby inducing systemic anti-tumor immunity. We previously reported favorable safety and preliminary efficacy of αPD-1-Ery in patients with PD-1/PD-L1–resistant solid tumors. Here, we report long-term follow-up results assessing durability of benefit and exploratory biomarkers. Methods: 14 heavily pretreated patients with 11 types of advanced solid tumors who had progressed on PD-1/PD-L1–containing regimens as their most recent line of therapy were enrolled. Patients received αPD-1-Ery monotherapy at 2×10¹¹ or 3×10¹¹ cells. Endpoints included safety, efficacy, and exploratory correlations between immune biomarkers and clinical outcomes. Results: As of October 31, 2025, all patients had completed treatment, with a median follow-up of 18.9 months. Treatment discontinuation occurred due to disease progression in 57.1% (8/14), CR in 7.1% (1/14), completion of planned treatment cycles in 21.4% (3/14), and other reasons (including AE or withdrawal) in 14.3% (2/14). No DLTs were observed. TRAEs occurred in 64.3% (9/14) of patients, with no grade >3 TRAEs, no grade ≥3 immune-related AEs, and no treatment discontinuations due to TRAEs. αPD-1-Ery demonstrated sustained anti-tumor activity, with a DCR of 78.6% (11/14) and an ORR of 42.9% (6/14; 1 CR, 1 uCR, 4 PR), with improved responses observed in the higher-dose cohort. mPFS was 5.6 months and mOS was 23.4 months. Durable benefit was observed in most responders, with 4/6 maintaining response after treatment discontinuation; 1 received no subsequent therapy and 3 resumed PD-1/PD-L1–based immunotherapy despite prior resistance. mDoR had not been reached (range, 4.8–24.7 months). Exploratory analyses indicated that clinical benefit was observed in both primary (n = 3) and acquired (n = 3) anti–PD-1/PD-L1–resistant patients. Responders had higher baseline circulating PMN-MDSCs and DCs and experienced rapid and sustained PMN-MDSC reduction following treatment. Tumor MMR status was available in 5 patients (all MSS), with objective responses observed in 3. Conclusions: Spleen-directed PD-1 blockade using erythrocyte–antibody conjugates induces durable clinical benefit. αPD-1-Ery represents a novel immunotherapeutic strategy for PD-1/PD-L1–resistant solid tumors and supports further clinical development. Clinical trial information: NCT06026605 .