Preclinical evaluation of PD-L1 targeted radiotherapy in a xenograft mouse model of triple-negative breast cancer

Abstract Background Targeted radiotherapy (TRT) against Programmed death-ligand 1 (PD-L1) in triple-negative breast cancer (TNBC) has been relatively unexplored and is a biologically available and radiosensitive target. Here, we assess the efficacy and safety of a PD-L1 TRT and quantify tumor and organ-specific distributions for the treatment of TNBC. Methods The PD-L1-targeting antibody atezolizumab was radiolabeled with lutetium-177. Athymic nude mice bearing high PD-L1 expressing MDA-MB-231 human TNBC tumors were treated with saline, 9.25 MBq, or 18.5 MBq of [ 177 Lu]Lu-atezolizumab, and Single photon emission computed tomography (SPECT) imaging was acquired. Dosimetry to organs was quantified following biodistributions at multiple timepoints post injection. Tumor volumes and body weight were monitored for 60 days, and relevant organs were H&E stained for pathological assessment. One- and two-way ANOVAs and log rank tests were utilized to assess differences between treatments. Results Both [ 177 Lu]Lu-atezolizumab doses significantly reduced tumor volume compared to control by day 20 (18.5 MBq, p < 0.05) or day 24 (9.25 MBq, p < 0.05) post-treatment and increased median survival (35 versus 52 and 60 days in control, 9.25 MBq and 18.5 MBq treated mice, respectively, p < 0.01). As expected with antibody-based radiopharmaceuticals, the liver was the highest dosed organ following [ 177 Lu]Lu-atezolizumab. No weight loss was observed in treated groups, and histology revealed minimal clearance organ toxicity. Conclusions [ 177 Lu]Lu-atezolizumab resulted in significantly decreased tumor volumes and increased survival in a mouse model of TNBC. This supports [ 177 Lu]Lu-atezolizumab as a novel TRT which has the potential to improve immunotherapy outcomes in TNBC.