Combined CD25-targeted near infrared photoimmunotherapy (NIR-PIT) and intratumor IL-15 enhance the effectiveness of anti-PD-1 immunotherapy

Immunotherapies aimed at enhancing anti-cancer immunity are now in wide clinical use. For instance, anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) therapy has demonstrated clinical efficacy in many tumor types, but overall, only a minority of patients respond. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that selectively destroys targeted cells. CD25-targeted NIR-PIT is a strategy that selectively depletes regulatory T cells in the tumor microenvironment, thereby enhancing the T-cell response of PD-1 mAbs. Cytokines, such as interleukin-15 (IL-15), can also modulate immune response by further activating CD8⁺ T cells, thereby creating favorable CD8⁺/Treg ratio.In this study, we evaluated the combination of CD25-targeted NIR-PIT and intratumoral IL-15 administration with anti-PD-1 mAb in treating syngeneic murine tumor models. The combination of CD25-targeted NIR-PIT and intratumoral IL-15 with anti-PD-1 mAb suppressed tumor growth, prolonged survival and increased the CD8⁺/Treg ratio. This combination achieved dramatic tumor control with 90% complete response and long-term survival, particularly in highly-immunogenic tumors. In addition, mice that achieved complete response resisted tumor re-inoculation suggesting durable memory T-cells were formed. In conclusion, the combination of CD25-targeted NIR-PIT and intratumoral IL-15 with anti-PD-1 therapy is a potentially useful strategy to improve the efficacy of immunotherapy.