Anti-Tumor Efficacy of PD-L1 Targeted Alpha-Particle Therapy in a Human Melanoma Xenograft Model.

Abstract

Simple SummaryIn recent years, the development of immune checkpoint inhibitors, such as anti-PD‑1 and anti-PD-L1, proved to prolong melanoma patient survival and are now used in routine clinical practice. PD-L1 also represents a potent biomarker for in vivo molecular imaging using radiolabeled anti-PD-L1 mAbs and positron emission tomography and is currently in development to select patients and assess response to treatment. The aim of our study was to investigate in a preclinical model of human melanoma if PD-L1 could also be a good target for treatment using targeted alpha-particle therapy. Our results show that targeting PD-L1 with bismuth-213, an alpha particle emitter, was associated with efficient anti-tumor response, significant tumor growth delay, and improved survival. This demonstrates that anti-PD-L1 antibodies could be used as theranostics in molecular imaging but also in targeted alpha-particle therapy to treat the tumor and its stroma.PD-L1 (programmed death-ligand 1, B7-H1, CD274), the ligand for PD-1 inhibitory receptor, is expressed on various tumors, and its expression is correlated with a poor prognosis in melanoma. Anti-PD-L1 mAbs have been developed along with anti-CTLA-4 and anti-PD-1 antibodies for immune checkpoint inhibitor (ICI) therapy, and anti-PD-1 mAbs are now used as first line treatment in melanoma. However, many patients do not respond to ICI therapies, and therefore new treatment alternatives should be developed. Because of its expression on the tumor cells and on immunosuppressive cells within the tumor microenvironment, PD-L1 represents an interesting target for targeted alpha-particle therapy (TAT). We developed a TAT approach in a human melanoma xenograft model that stably expresses PD-L1 using a 213Bi-anti-human-PD-L1 mAb. Unlike treatment with unlabeled anti-human-PD-L1 mAb, TAT targeting PD-L1 significantly delayed melanoma tumor growth and improved animal survival. A slight decrease in platelets was observed, but no toxicity on red blood cells, bone marrow, liver or kidney was induced. Anti-tumor efficacy was associated with specific tumor targeting since no therapeutic effect was observed in animals bearing PD-L1 negative melanoma tumors. This study demonstrates that anti-PD-L1 antibodies may be used efficiently for TAT treatment in melanoma.