Dual activity of PD-L1 targeted Doxorubicin immunoliposomes promoted an enhanced efficacy of the antitumor immune response in melanoma murine model

Journal of Nanobiotechnology

Hugo Lana¹  María Merino¹  Sara Zalba²  María J. Garrido²  Iñaki F. Troconiz²  Timo L. M. ten Hagen³  Grazyna Kochan⁴  Teresa Lozano⁵  Pedro Berraondo⁵  Noelia Casares⁵ 

[1] Department of Pharmaceutical Technology and Chemistry, School of Pharmacy, University of Navarra, 31008, Pamplona, Navarra, Spain;Department of Pharmaceutical Technology and Chemistry, School of Pharmacy, University of Navarra, 31008, Pamplona, Navarra, Spain;Navarra Institute for Health Research (IdisNA), Pamplona, Spain;Laboratory of Experimental Oncology, Erasmus Medical Center, Rotterdam, The Netherlands;Navarra Institute for Health Research (IdisNA), Pamplona, Spain;Department of Oncology, Navarrabiomed-Biomedical Research Centre, Pamplona, Spain;Program of Immunology and Immunotherapy, CIMA-Universidad de Navarra, Pamplona, Spain;Navarra Institute for Health Research (IdisNA), Pamplona, Spain;

关键词: Liposome;    PD-L1;    Doxorubicin;    Chemo-immunotherapy;    Immunotherapy;    Immunogenic cell death;    Melanoma;    Immunocheckpoint;   

DOI  :  10.1186/s12951-021-00846-z

来源: Springer

【 摘 要 】

BackgroundThe immunomodulation of the antitumor response driven by immunocheckpoint inhibitors (ICIs) such as PD-L1 (Programmed Death Ligand-1) monoclonal antibody (α-PD-L1) have shown relevant clinical outcomes in a subset of patients. This fact has led to the search for rational combinations with other therapeutic agents such as Doxorubicin (Dox), which cytotoxicity involves an immune activation that may enhance ICI response. Therefore, this study aims to evaluate the combination of chemotherapy and ICI by developing Dox Immunoliposomes functionalized with monovalent-variable fragments (Fab’) of α-PD-L1.ResultsImmunoliposomes were assayed in vitro and in vivo in a B16 OVA melanoma murine cell line over-expressing PD-L1. Here, immune system activation in tumor, spleen and lymph nodes, together with the antitumor efficacy were evaluated. Results showed that immunoliposomes bound specifically to PD-L1+ cells, yielding higher cell interaction and Dox internalization, and decreasing up to 30-fold the IC50, compared to conventional liposomes. This mechanism supported a higher in vivo response. Indeed, immunoliposomes promoted full tumor regression in 20% of mice and increased in 1 month the survival rate. This formulation was the only treatment able to induce significant (p < 0.01) increase of activated tumor specific cytotoxic T lymphocytes at the tumor site.ConclusionPD-L1 targeted liposomes encapsulating Dox have proved to be a rational combination able to enhance the modulation of the immune system by blocking PD-L1 and selectively internalizing Dox, thus successfully providing a dual activity offered by both, chemo and immune therapeutic strategies.Graphic Abstract

【 授权许可】

CC BY