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

Background and purposePARP 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 beta-emitting Lu-177-NNV003 radioimmunotherapy and the PARP inhibitor olaparib, and gene expression profiles in CD37 positive non-Hodgkin's lymphoma cell lines. Materials and methodsThe combined effect of Lu-177-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. ResultsThe combination of olaparib and Lu-177-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 Lu-177-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. ConclusionThe cytotoxic effect of the combination of the PARP inhibitor olaparib and the beta-emitting radioimmunoconjugate Lu-177-NNV003 was synergistic in the majority of tested lymphoma cell lines.

Automated summary

The combination of olaparib and Lu-177-NNV003 showed synergistic cytotoxic effects in the majority of tested lymphoma cell lines, with some exhibiting both synergistic and antagonistic effects depending on concentration ratios. Treatment with the combination resulted in significant overexpression of genes in the TP53 signaling pathway. However, cluster analysis did not identify gene clusters correlating with cell sensitivity to single or combination treatments.