Abstract 3052: Combining α-particle radiopharmaceutical therapy using Actinium-225 and immunotherapy with anti-PD-L1 antibodies in a murine immunocompetent metastatic breast cancer model
Authors: Anders Josefsson, Jessie R. Nedrow, Sunju Park, Sagar Ranka, George Sgouros
Journal: Cancer Research (2016)

Abstract The programmed cell death ligand 1 (PD-L1) plays an essential role in suppressing immune recognition of cancer. PD-L1 is expressed on a variety of cells including tumor cells, tumor associated macrophages (TAMs) and other cells within the microenvironment of the tumor. When PD-L1 binds to the programmed death 1 (PD-1) receptor it inhibits CD8+ T-cell effector function. By upregulating the expression levels of PD-L1, tumor cells and TAMs are capable of avoiding T-cell immune recognition. Immunotherapy using anti-PD-L1 antibody (Ab) has shown promising anti-tumor effect against a number of cancers including breast cancer, and is currently used in several clinical trials. Furthermore, studies have shown that anti-PD-L1 Ab targeted immunotherapy synergizes with radiation therapy. The aim of this study was to investigate a possible gain in therapeutic efficacy when combining targeted α-particle radiopharmaceutical therapy using 225Ac with anti-PD-L1 Ab immunotherapy in a murine immunocompetent metastatic breast cancer model. 6-8 week old healthy female neu-N mice were injected in the left cardiac ventricle (LCV) with 50,000 NT2.5 (endogenously derived) tumor cells to create highly aggressive widespread breast cancer metastases. Groups (n = 8) of mice were injected intravenously (i.v.) in the tail vein 72 h after the LCV injection with either 1) a single dose of 300 or 400 nCi 225Ac-DOTA-anti-PD-L1 Ab (0.15 mg/kg), 2) a single dose of 100 times (100x) anti-PD-L1 Ab (15.9 mg/kg) or 3) a 400 nCi single dose 225Ac-DOTA-anti-PD-L1 Ab (0.15 mg/kg) in combination with a single dose of 100x anti-PD-L1 Ab (16.1 mg/kg). The mice in the control group were injected i.v. in the tail vein with 100 μl of saline. The 225Ac-DOTA-anti-PD-L1 conjugate was radiolabeled having a specific activity of 0.137 μCi/μg with a radiochemical purity &amp;gt;95%. The group receiving the single dose of 100x anti-PD-L1 Ab had the highest median survival of 44 days (p = 0.0007) followed by the 400 nCi 225Ac-DOTA-anti-PD-L1 Ab group with 39.5 days (p = 0.0413) compared with the control group 31.5 days. The survival for other treatment groups were not significant compared with the control group. Furthermore, the survival from the single dose of 100x anti-PD-L1 Ab treatment was significantly higher than the single dose treatment of 400 nCi 225Ac-DOTA-anti-PD-L1 Ab (p = 0.0308). The highest survival rate was the mice treated with 100x anti-PD-L1 Ab. The combination treatment using 400 nCi 225Ac-DOTA-anti-PD-L1 Ab and 100x anti-PD-L1 Ab showed a significant lower survival compared to each treatment by itself. However, the combination treatment was only performed with one dose and the injection was at the same time, different concentrations and time spaced injections could possibly favor the combined treatment method over the single modality treatments. Citation Format: Anders Josefsson, Jessie R. Nedrow, Sunju Park, Sagar Ranka, George Sgouros. Combining α-particle radiopharmaceutical therapy using Actinium-225 and immunotherapy with anti-PD-L1 antibodies in a murine immunocompetent metastatic breast cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3052.