The dual PI3Kdelta/CK1epsilon inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells.

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Maharaj K, Powers JJ, Achille A, Mediavilla-Varela M, Gamal W, Burger KL, Fonseca R, Jiang K, Miskin HP, Maryanski D, Monastyrskyi A, Duckett DR, Roush WR, Cleveland JL, Sahakian E, Pinilla-Ibarz J

The dual PI3Kdelta/CK1epsilon inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells.

Blood Adv. 2020 Jul 14;4(13):3072-3084. doi: 10.1182/bloodadvances.2020001800.

PubMed ID

32634240 [ View in PubMed

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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 PI3Kdelta/casein kinase-1-epsilon (CK1epsilon) 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 Emu-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 Emu-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 CK1epsilon can improve CLL Treg number and function. Interestingly, CK1epsilon 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 PI3Kdelta/CK1epsilon inhibitor that preserves Treg number and function.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Umbralisib	Casein kinase I isoform epsilon	Protein	Humans	Yes	Inhibitor	Details
Umbralisib	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	Protein	Humans	Yes	Inhibitor	Details