Nie, Liu, Yao, et al. developed an erythrocyte–antibody conjugate in which anti-PD-1 antibodies were covalently linked to erythrocyte membranes (αPD1-Ery). These cellular-Ab conjugates accumulated in spleens, where they expanded effector T cells and reduced immunosuppressive myeloid cells, leading to reduced tumor growth in mouse models. In a first-in-human phase I clinical trial, 14 patients with advanced cancers who were resistant to anti-PD-1/L1 were treated at 2 dose levels, which were well tolerated and reduced circulating immunosuppressive myeloid cells. The ORR was 42.9%, with 1 CR and 5 PRs, and the DCR was 78.6%.
Contributed by Lauren Hitchings
ABSTRACT: Despite the clinical success of immune checkpoint blockade therapy, most persons do not benefit because of inadequate efficacy, primary or acquired resistance and/or immune-related toxicities. Here we developed an erythrocyte-antibody conjugate in which anti-PD1 antibodies are covalently linked to erythrocyte membranes (αPD1-Ery). Unlike conventional antibodies, αPD1-Ery accumulates in the spleen, where it remodels the immune landscape by expanding effector T cells and reducing immunosuppressive myeloid cells. These changes reprogram the tumor microenvironment and suppress tumor growth in syngeneic mouse models. We conducted a first-in-human, phase 1 clinical trial of αPD1-Ery monotherapy in persons with advanced cancers resistant to prior anti-PD1/PDL1 therapy ( NCT06026605 ). The primary objective was safety; secondary objectives included efficacy, pharmacokinetics, pharmacodynamics and immunogenicity. A total of 14 participants were enrolled, with 7 receiving 2 × 1011 cells and 7 receiving 3 × 1011 cells. Repeated administration resulted in no dose-limiting toxicities or treatment-related adverse events of grade >3. The objective response rate was 42.9%, including 1 complete response and 5 partial responses; disease control rate was 78.6%. Notably, αPD1-Ery rapidly reduced circulating immunosuppressive myeloid cells, consistent with preclinical observations. The study met its prespecified primary and secondary endpoints. These findings support spleen-targeted PD1 blockade by erythrocyte-antibody conjugates as a potential strategy for cancer immunotherapy.
Author Info: (1) School of Basic Medical Sciences, Fudan University, Shanghai, China. Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Science
Author Info: (1) School of Basic Medical Sciences, Fudan University, Shanghai, China. Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China. (2) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China. (3) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China. (4) The Key Laboratory of Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (5) School of Basic Medical Sciences, Fudan University, Shanghai, China. Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China. (6) Westlake Therapeutics, Hangzhou, China. (7) Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. yxfeng@zju.edu.cn. Cancer Center, Zhejiang University, Hangzhou, China. yxfeng@zju.edu.cn. (8) The Key Laboratory of Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. liangtingbo@zju.edu.cn. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. liangtingbo@zju.edu.cn. (9) Department of Oncology, Zhejiang Provincial People's Hospital, Hangzhou, China. yangliu@hmc.edu.cn. (10) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China. gaoxiaofei@westlake.edu.cn. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. gaoxiaofei@westlake.edu.cn. Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China. gaoxiaofei@westlake.edu.cn. Research Center for Industries of the Future and School of Engineering, Westlake University, Hangzhou, China. gaoxiaofei@westlake.edu.cn.
