A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity

Despite the demonstrated immense potential of immune checkpoint inhibitors in various types of cancers, only a minority of patients respond to these therapies. Immunocytokines designed to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME) and block the immune checkpoint simultaneously may provide a strategic advantage over the combination of two single agents. To increase response rate to checkpoint blockade, in this study we developed a novel immunocytokine (LH01) composed of the antibody against programmed death-ligand 1 (PD-L1) fused to IL-15 receptor alpha-sushi domain/IL-15 complex. We demonstrate that LH01 efficiently binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. In syngeneic mouse models, LH01 showed improved antitumor efficacy and safety versus anti-PD-L1 plus LH02 (Fc-Sushi-IL15) combination and overcame resistance to anti-PD-L1 treatment. Mechanistically, the dual anti-immunosuppressive function of LH01 led to activation of both the innate and adaptive immune response and decreased levels of transforming growth factor-β1 (TGF-β1) within the TME. Furthermore, combination therapy with LH01 and bevacizumab exerts synergistic antitumor effects in HT29 colorectal xenograft model. Collectively, our results provide supporting evidence that fusion of anti-PD-L1 and IL-15 might be a potent strategy to treat patients with cold tumors or resistance to checkpoint blockade. ### Competing Interest Statement The authors have declared no competing interest.