ArticleBlood advances2020
The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells.
Article in Blood advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
43 citing papers in PubMed, 2 syntheses or guidelines pooled it, 63 citations in OpenAlex.
- Clinical efficacy and safety of umbralisib, a dual PI3Kδ/CK1-ϵ inhibitor, in treatment of hematologic malignancies.Frontiers in oncology · 2025Pooled it
- Response to therapy in Richter syndrome: a systematic review with meta-analysis of early clinical trials.Frontiers in immunology · 2023Pooled it
- Protein Profiles Predict Treatment Responses to the PI3K Inhibitor Umbralisib in Patients with Chronic Lymphocytic Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies.Blood advances · 2021Trial
- Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2021Trial
- Trial
- Casein kinase 1δ/ε inhibition suppresses CLL proliferation through cell-intrinsic and microenvironmental mechanisms.HemaSphere · 2026Article
- The Development of Novel Therapies for Chronic Lymphocytic Leukaemia in the Era of Targeted Drugs.Journal of clinical medicine · 2025Review
- Mitigating T-cell mitochondrial dysfunction in CLL to augment CAR T-cell therapy: evaluation in an immunocompetent model.Blood advances · 2025Article
- Long-term results of a phase 1/1b study of ibrutinib plus umbralisib for relapsed/refractory chronic lymphocytic leukemia.HemaSphere · 2025Article
- Promises of Protein Kinase Inhibitors in Recalcitrant Small-Cell Lung Cancer: Recent Scenario and Future Possibilities.Cancers · 2024Review
- Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway.Journal of translational medicine · 2024Review
- Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas.World journal of gastroenterology · 2023Review
- CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade.Nature communications · 2023Article
- T Cell-intrinsic Immunomodulatory Effects of TAK-981 (Subasumstat), a SUMO-activating Enzyme Inhibitor, in Chronic Lymphocytic Leukemia.Molecular cancer therapeutics · 2023Article
- Recent advances in treatment of nodal and gastrointestinal follicular lymphoma.World journal of gastroenterology · 2023Article
- Simultaneous Inhibition of PI3Kgamma and PI3Kdelta Deteriorates T-cell Function With Implications for Chronic Lymphocytic Leukemia.HemaSphere · 2023Article
- Development and safety of PI3K inhibitors in cancer.Archives of toxicology · 2023Review
- Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors.Blood cancer journal · 2023Article
- PI3K inhibitors in chronic lymphocytic leukemia: where do we go from here?Haematologica · 2023Review
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
Abstract
The in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response and progression-free survival in clinical trials of B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a high incidence of adverse events has led to frequent discontinuations, limiting the clinical development of these inhibitors. By contrast, the dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows high rates of response in clinical trials but has an improved safety profile with fewer severe adverse events. Toxicities typical of this class of PI3K inhibitors are largely thought to be immune mediated, but they are poorly characterized. Here, we report the effects of idelalisib, duvelisib, and umbralisib on regulatory T cells (Tregs) on normal human T cells, T cells from CLL patients, and T cells in an Eμ-TCL1 adoptive transfer mouse CLL model. Ex vivo studies revealed differential effects of these PI3K inhibitors; only umbralisib treatment sustained normal and CLL-associated FoxP3+ human Tregs. Further, although all 3 inhibitors exhibit antitumor efficacy in the Eμ-TCL1 CLL model, idelalisib- or duvelisib-treated mice displayed increased immune-mediated toxicities, impaired function, and reduced numbers of Tregs, whereas Treg number and function were preserved in umbralisib-treated CLL-bearing mice. Finally, our studies demonstrate that inhibition of CK1ε can improve CLL Treg number and function. Interestingly, CK1ε inhibition mitigated impairment of CLL Tregs by PI3K inhibitors in combination treatment. These results suggest that the improved safety profile of umbralisib is due to its role as a dual PI3Kδ/CK1ε inhibitor that preserves Treg number and function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.