Combined Melanin-Targeted Radionuclide Therapy and Immunotherapy in Pigmented Advanced Malignant Melanoma.

The benzamide analogue 131I-N-(2-(diethylamino)ethyl)-5-(iodo-131I) picolinamide (131I-5-IPN) was developed for targeted radionuclide therapy (TRNT) of pigmented melanoma and showed good pharmacokinetics and a high melanin-binding affinity. Our aim was to investigate the antitumor efficacy of 131I-5-IPN alone and in combination with immunotherapy in pigmented advanced malignant melanoma. 131I-5-IPN was synthesized and purified. Pigmented (B16F10) and nonpigmented (A375m) melanoma cell lines were used to assess binding in vitro and to establish mouse melanoma models. Static 131I-5-IPN SPECT/CT imaging was performed in tumor-bearing subcutaneous and lung metastasis model mice. B16F10-bearing subcutaneous and lung metastasis mouse models were treated with 131I-5-IPN TRNT alone or 131I-5-IPN in combination with anti-PD-L1 antibody. The tumor volume, mice weight, and survival time were recorded. The tumors were harvested and analyzed by immunofluorescence and flow cytometry. 131I-5-IPN was successfully synthesized with a high radiochemical yield of 60-70%, demonstrating high affinity and specificity for B16F10 cells both in vitro and in vivo. Pronounced accumulation of 131I-5-IPN in B16F10 subcutaneous tumors and lung metastases was confirmed in the biodistribution study, with high tumor-to-muscle ratios reaching 45.91 ± 21.17 and 55.99 ± 21.08 at 24 and 48 h, respectively. B16F10 subcutaneous tumor growth was significantly reduced in mice treated with 131I-5-IPN TRNT alone or 131I-5-IPN combined with anti-PD-L1 antibody; both groups showed extended median survival compared with control mice. For lung metastases treatment, mice treated with 131I-5-IPN TRNT alone or TRNT combined with anti-PD-L1 group had a significantly extended median survival time (22 and 31 d, respectively) compared with control group mice (15 d) (p < 0.001). No significant histopathological evidence of hepatic or kidney injury was observed during treatment. 131I-5-IPN specifically targeted melanin with a high retention and affinity in vitro and in vivo. The 131I-5-IPN TRNT combination with anti-PD-L1 antibody maybe a potential new therapy for pigmented advanced malignant melanoma.