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Immunoregulatory effects of Lurbinectedin in chronic lymphocytic leukemia
Denise Risnik1, Ana Colado2, Enrique Podaza2
1Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, 1425, Buenos Aires, Argentina. risnikd@upmc.edu.
Abstract:
Despite significant therapeutic improvements chronic lymphocytic leukemia (CLL) remains an incurable disease and there is a persistent pursuit of new treatment alternatives. Lurbinectedin, a selective inhibitor of active transcription of protein-coding genes, is currently in phase II/III clinical trials for solid tumors such as small-cell lung cancer (SCLC). In this study, we aimed to evaluate the activity of Lurbinectedin on circulating mononuclear cells from CLL patients and to determine whether Lurbinectedin could affect the cross-talk between B-CLL cells and the tumor microenvironment. We found that Lurbinectedin induced a dose- and time-dependent death in all cell types evaluated, with B cells, monocytes and monocytic myeloid derived suppressor cells (Mo-MDSC) being the most susceptible populations. At sub-apoptotic doses, Lurbinectedin decreased the expression of CCR7 in B-CLL cells and impaired their migration towards CCL19 and CCL21. Furthermore, low concentrations of Lurbinectedin stimulated the synthesis of pro-IL1β in monocytes and nurse-like cells, without inducing the inflammasome activation. Altogether, these results indicate that Lurbinectedin might have antitumor activity in CLL due to its direct action on leukemic cells in combination with its effects on the tumor microenvironment. Our findings encourage further investigation of Lurbinectedin as a potential therapy for CLL.
Insights
Lurbinectedin shows promise for treating chronic lymphocytic leukemia (CLL) by directly killing cancer cells and modulating the tumor microenvironment. Further research is encouraged for this potential new CLL therapy.
Area of Science:
- Oncology
- Hematology
- Pharmacology
Background:
- Chronic lymphocytic leukemia (CLL) remains incurable despite therapeutic advances.
- There is an ongoing need for novel CLL treatment strategies.
- Lurbinectedin is an established transcription inhibitor investigated for solid tumors.
Purpose of the Study:
- To assess Lurbinectedin's activity against CLL cells and associated microenvironment.
- To investigate Lurbinectedin's impact on B-CLL cell and tumor microenvironment interactions.
Main Methods:
- Evaluation of Lurbinectedin's cytotoxic effects on CLL patient mononuclear cells.
- Assessment of Lurbinectedin's influence on B-CLL cell migration and pro-inflammatory cytokine synthesis in monocytes.
Main Results:
- Lurbinectedin induced dose- and time-dependent cell death in CLL mononuclear cells, particularly B cells, monocytes, and monocytic myeloid-derived suppressor cells (Mo-MDSC).
- Sub-apoptotic doses of Lurbinectedin reduced B-CLL cell migration and stimulated pro-IL1β synthesis in monocytes without inflammasome activation.
- Lurbinectedin demonstrated direct cytotoxicity and microenvironmental modulation relevant to CLL.
Conclusions:
- Lurbinectedin exhibits potential antitumor activity in CLL through direct leukemic cell effects and microenvironment modulation.
- These findings support further investigation of Lurbinectedin as a therapeutic option for CLL.
- Lurbinectedin's dual action warrants continued exploration in CLL treatment strategies.
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