Melanoma incidence continues to rise, and while therapeutic approaches for early stage cases are effective, metastatic
melanoma continues to be associated with high mortality.
Immune checkpoint blockade (ICB) has demonstrated clinical success with approved drugs in cohorts of patients with metastatic
melanoma and targeted
radionuclide therapy strategies showed promise in several clinical trials against various
cancers including metastatic
melanoma. This led our group to investigate the combination of these two treatments which could be potentially offered to patients with metastatic
melanoma not responsive to ICB alone. Previously, we have demonstrated that a combination of humanized anti-
melanin antibody conjugated to 213Bismuth and anti-PD-1 ICB reduced
tumor growth and increased survival in the Cloudman S91 murine
melanoma DBA/2 mouse model. In the current study, we sought to improve the tumoricidal effect by using the long-lived
radionuclides 177Lutetium and 225Actinium. Male Cloudman S91-bearing DBA/2 mice were treated intraperitoneally with PBS (
Sham), unlabeled antibody to
melanin, anti-PD-1 ICB, 177Lutetium or 225Actinium RIT, or a combination of ICB and RIT. Treatment with anti-PD-1 alone or low-dose 177Lutetium RIT alone resulted in modest
tumor reduction, while their combination significantly reduced
tumor growth and increased survival, suggesting synergy. 225Actinium RIT, alone or in combination with ICB, showed no therapeutic benefit, suggesting that the two
radionuclides with different energetic properties work in distinct ways. We did not detect an increase in
tumor-infiltrating T cells in the tumor microenvironment, which suggests the involvement of alternative mechanisms that improve the effect of combination
therapy beyond that observed in the single
therapies.