Depletion of Soluble PD-L1 with Engineered Nanoparticles Promotes Antitumor Immunity and Tumor Control.

PURPOSE: Programmed Cell Death Protein 1 (PD-1) and Programmed Cell Death Ligand 1 (PD-L1) checkpoint blockade has led to improvements in clinical outcomes for various advanced cancers. However, response rates remain low, and most patients present with intrinsic resistance to PD-1/PD-L1 inhibitors. Circulating soluble PD-L1 (sPD-L1) has emerged as a driver of resistance to PD-1/PD-L1 inhibitors. Elevated levels of sPD-L1 can be detected in peripheral blood in patients with cancer and are associated with poor prognosis and resistance to PD-1/PD-L1 therapy, highlighting the need to find strategies to remove sPD-L1 from circulation. Here, we evaluated the efficacy and immunological responses of using NaNots®A, a type of engineered nanoparticle that has been designed to capture sPD-L1, as a therapeutic agent to treat cancer. METHODS: Different biological samples containing sPD-L1 were tested pre- and post-treatment to determine the capturing efficiency of NaNots. To evaluate the therapeutic potential of NaNots in vivo, a humanized PD-L1 mouse model was used with an sPD-L1 secreting tumor model to assess tumor growth and to immunophenotype antitumor responses. RESULTS: NaNot treatment successfully depleted sPD-L1 from multiple sources, including patient and mouse plasma. NaNot treatment resulted in substantial tumor growth delay and increased proportions of effector CD8 T cells, concurrent with decreased immunosuppressive regulatory T cells, in tumor and spleen tissues. CONCLUSION: Overall, this preclinical work demonstrates that selective capture of sPD-L1 in vivo with a novel nanotherapeutic platform can reduce immune suppression concurrent with greater immune activation, thereby enabling tumor growth control.