Immune checkpoint inhibition improves antimyeloma activity of bortezomib and STING agonist combination in Vk*MYC preclinical model.

ABSTRACT

Multiple myeloma (MM), a hematological malignancy of plasma cells, has remained incurable despite the development of novel therapies that improve patients' outcome. Recent evidence indicates that the stimulator of interferon genes (STING) pathway may represent a novel target for induction of antitumor immune response in multiple myeloma. Here, we investigated antitumor effects of STING agonist with bortezomib with or without checkpoint inhibitor in the treatment of MM. METHODS: STING expression in bone marrow plasma cells of 58 MM patients was examined by immunohistochemical staining. The effectiveness of the proposed therapy was evaluated in vivo in a syngeneic transplantable mouse model of MM (Vĸ*MYC) in immunocompetent mice. Flow cytometry was used to assess tumor burden and investigate activation of immune response against MM. ELISA was performed to measure serum inflammatory cytokines concentrations upon treatment. RESULTS: Combining a STING agonist [2'3'-cGAM(PS)2] with bortezomib significantly decreased tumor burden and improved the survival of treated mice compared to either of the compounds used alone. The combination treatment led to secretion of pro-inflammatory cytokines and increased the percentage of neutrophils, activated dendritic cells and T cells in the tumor microenvironment. However, it resulted also in increased expression of PD-L1 on the surface of the immune cells. Addition of anti-PD1 antibody further potentiated the therapeutic effects. CONCLUSIONS: Our findings indicate high antimyeloma efficacy of the three-drug regimen comprising bortezomib, STING agonist, and a checkpoint inhibitor.