Anti-CD37 radioimmunotherapy with 177Lu-NNV003 synergizes with the PARP inhibitor olaparib in treatment of non-Hodgkin's lymphoma in vitro.

Background and purpose: PARP inhibitors have been shown to increase the efficacy of radiotherapy in preclinical models. Radioimmunotherapy results in selective radiation cytotoxicity of targeted tumour cells. Here we investigate the combined effect of anti-CD37 β-emitting ¹⁷⁷Lu-NNV003 radioimmunotherapy and the PARP inhibitor olaparib, and gene expression profiles in CD37 positive non-Hodgkin's lymphoma cell lines. Materials and methods: The combined effect of ¹⁷⁷Lu-NNV003 and olaparib was studied in seven cell lines using a fixed-ratio ray design, and combination index was calculated for each combination concentration. mRNA was extracted before and after treatment with the drug combination. After RNA-sequencing, hierarchical clustering was performed on basal gene expression profiles and on differentially expressed genes after combination treatment from baseline. Functional gene annotation analysis of significant differentially expressed genes after combination treatment was performed to identify enriched biological processes. Results: The combination of olaparib and ¹⁷⁷Lu-NNV003 was synergistic in four of seven cell lines, antagonistic in one and both synergistic and antagonistic (conditionally synergistic) in two, depending on the concentration ratio between olaparib and ¹⁷⁷Lu-NNV003. Cells treated with the combination significantly overexpressed genes in the TP53 signalling pathway. However, cluster analysis did not identify gene clusters that correlate with the sensitivity of cells to single agent or combination treatment. Conclusion: The cytotoxic effect of the combination of the PARP inhibitor olaparib and the β-emitting radioimmunoconjugate ¹⁷⁷Lu-NNV003 was synergistic in the majority of tested lymphoma cell lines. [ABSTRACT FROM AUTHOR]