CD137 agonist potentiates the abscopal efficacy of nanoparticle-based photothermal therapy for melanoma.

Despite the promise of immunotherapy such as the immune checkpoint inhibitors (ICIs) anti-PD-1 and anti-CTLA-4 for advanced melanoma, only 26%-52% of patients respond, and many experience grade III/IV immune-related adverse events. Motivated by the need for an effective therapy for patients non-responsive to clinically approved ICIs, we have developed a novel nanoimmunotherapy that combines locally administered Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) with systemically administered agonistic anti-CD137 monoclonal antibody therapy (aCD137). PBNP-PTT was administered at various thermal doses to melanoma cells , and was combined with aCD137 to test treatment effects on melanoma tumor progression, animal survival, immunological protection against tumor rechallenge, and hepatotoxicity. When administered at a melanoma-specific thermal dose, PBNP-PTT elicits immunogenic cell death (ICD) in melanoma cells and upregulates markers associated with antigen presentation and immune cell co-stimulation . Consequently, PBNP-PTT eliminates primary melanoma tumors , yielding long-term tumor-free survival. However, the antitumor immune effects generated by PBNP-PTT cannot eliminate secondary tumors, despite significantly slowing their growth. The addition of aCD137 enables significant abscopal efficacy and improvement of survival, functioning through activated dendritic cells and tumor-infiltrating CD8 T cells, and generates CD4 and CD8 T cell memory that manifests in the rejection of tumor rechallenge, with no long-term hepatotoxicity. This study describes for the first time a novel and effective nanoimmunotherapy combination of PBNP-PTT with aCD137 mAb therapy for melanoma.