The marine-derived compound trabectedin depletes both human primary leukemic cells and myeloid-derived suppressor cells, according to a new study published in Cancer Immunology Research.1 The researchers think their findings could lead to a new therapy that targets both leukemic cells and the protumor microenvironment, repairing the immune dysfunction that is characteristic of chronic lymphocytic leukemia (CLL).

CLL is characterized by lymphocyte accumulation in the blood, bone marrow, and lymphoid tissues.2 Recent advances in CLL therapy have come from finding and targeting the appropriate molecular pathways of the disease, explained Kanti R. Rai, MD, a professor of medicine and molecular medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell who wasn’t involved in the study. Dr Rai said that, for instance, the Bruton tyrosine kinase inhibitor ibrutinib binds to the receptor and affects B-cell–receptor signaling. Another drug, venetoclax, an antagonist to BCL2, can effectively induce apoptosis in CLL cells. However, treatment of this disease remains challenging due to its immunosuppressive nature. “If we [are] to attain a cure, newer compounds have to be identified which have a different mechanism of controlling CLL,” he said.

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Patients with CLL have dysfunctional T cells, noted Maria Teresa Bertilaccio, PhD, who is an assistant professor in the department of experimental therapeutics at The University of Texas MD Anderson Cancer Center in Houston, and the corresponding author of the study. “Patients [with CLL] have immunosuppression features, so they might develop an infection because their immune system is not working,” she told Cancer Therapy Advisor. “Our approach is not only to eradicate leukemia, but also to rearm the immune system to give patients a better quality of life.”

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Trabectedin targets tumor-associated macrophages (TAMs); TAMs are thought to support CLL growth. A previous study by the Bertilaccio group showed that depleting TAMs by blocking CSF1R signaling reprograms the tumor microenvironment toward an antitumor phenotype.3 This led them to hypothesize that trabectedin could simultaneously target both leukemic cells and nonmalignant cells in the tumor microenvironment.