Evaluation of the combination of lurbinectedin and atezolizumab in a humanized mouse model.

Abstract

e14614 Background: Lurbinectedin, a synthetic ectenaiscidin approved by the FDA in 2020 for the treatment of extensive small cell lung cancer (SCLC) after progression to platinum, targets tumors with high transcriptional activity while enhancing anti-tumor immunity by inducing immunogenic cell death. In syngeneic SCLC mouse models, it effectively reverses resistance to first-line Pt-etoposide-anti-PD-L1 therapy when combined with anti-PD-L1, emulating clinical treatment scenarios. Methods: Humanized NXG-HIS mice were developed using busulfan chemoablation and CD34+ cord blood cell transplantation. These mice, inoculated with the MDA-MB-231 breast cancer cell line (a suitable model for studying immune combinations), were treated with lurbinectedin (0.18 mg/kg on days 0, 7 and 14 I.V.), atezolizumab (anti-PD-L1, 10 mg/kg on days 0, 2, 7, 9, 14 and 16 I.P.), or their combination to study immune therapies. Tumor growth was monitored alongside cytometry analysis of immune cells infiltration, with bulk RNA sequencing and cell type enrichment analysis (XCell Tool) used to characterize the tumors and their immune microenvironment. Results: Lurbinectedin showed high antitumor efficacy as a single agent, while atezolizumab had moderate activity. On Day 21, their combination resulted in significantly enhanced antitumor activity compared to either monotherapy (p = 0.0079 vs. atezolizumab; p = 0.0317 vs. lurbinectedin). On Day 28, flow cytometry revealed that lurbinectedin increased anti-tumoral immune cells (CD8+ T cells, NK cells, CD4+ T cells, M1 macrophages and dendritic cells) while reducing pro-tumoral and immunesuppressive cells (M2-macrophages or regulatory T cells). These effects were minimal with atezolizumab alone but amplified in the combination treatment. RNA-seq analysis confirmed enhanced immune infiltration, inflammatory and interferon responses, and an increase in HLA class I expression, boosting tumor antigenicity. Furthermore, lurbinectedin and the combination suppressed critical tumor pathways, including the cell cycle, epithelial-mesenchymal transition, and Myc signaling, suggesting a dual mechanism of action: direct tumor inhibition and immune-mediated effects. Conclusions: Lurbinectedin directly targets tumors by blocking their transcriptional profile, recruiting anti-tumoral immune cells, and enhancing tumor antigenicity. Consequently, it mitigates tumor immune evasion, “warming” the immune tumor microenvironment and sensitizing to atezolizumab treatment in combination.