Idelalisib reduces regulatory T cells and activates T helper 17 cell differentiation in relapsed refractory patients with chronic lymphocytic leukaemia

Gadi, Deepti; Griffith, Alec; Wang, Zixu; Tyekucheva, Svitlana; Rai, Vanessa; Fernandes, Stacey M.; Machado, John-Hanson; Munugalavadla, Veerendra; Lederer, James A.; Brown, Jennifer R.

doi:10.1111/bjh.18053

Cited by 8 publications

(15 citation statements)

References 15 publications

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“…Th2 differentiation was increased by idelalisib without a signi cant effect of duvelisib. These data are consistent with the changes we have previously seen in vivo with CyTOF analysis of CLL patient PBMCs 16,17,23 .…”

Section: Impact Of Idelalisib and Duvelisib On T Cells In Vitrosupporting

confidence: 92%

“…Our initial results evaluating T cell alterations in patients treated with PI3Kδ inhibitors demonstrated that T regulatory cells (Tregs) decreased early after idelalisib initiation, particularly in patients who developed toxicity 2,20 . Our initial mass cytometry by time-of-ight (CyTOF) investigations also suggested that the Th17 pathway was activated in patients with toxicity 17 . We therefore undertook the studies presented here, to assess the impact of both idelalisib and duvelisib on T cells in vitro, and to directly evaluate the Th17 pathway using patient samples from both of these trials, both in peripheral blood and tissues.…”

Section: Introductionmentioning

confidence: 93%

“…Duvelisib was approved in 2018, also for CLL after at least two prior therapies 15 , but has had similar toxicity 15 . The preclinical data suggest that these two drugs of different isoform speci cities may differ in the mechanism of autoimmune toxicity, but data to date remain limited 16,17 .…”

Section: Introductionmentioning

confidence: 99%

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Circulating Th17 T Cells at Treatment Onset Predict Autoimmune Toxicity of PI3Kδ Inhibitors

Gadi

Martindale

Chiu

et al. 2022

Preprint

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PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity, despite promising efficacy and evidence that toxicity is associated with improved clinical outcomes. Prior phenotypic evaluation by CyTOF has identified increases in activated CD8 T cells with activation of Th17 T cells, as well as decreases in Tregs, particularly in patients with toxicity. Here we sought to further understand the effects of idelalisib and duvelisib in vitro, and demonstrate that both idelalisib and duvelisib can inhibit T cell proliferation as well as Th1 and Treg differentiation in vitro, while promoting Th2 and Th17 differentiation. We further demonstrate directly using intracellular flow cytometry that autoimmune toxicity in patients is associated with higher absolute numbers of CD4 and CD8 T cells with Th17 differentiation in peripheral blood prior to therapy, and that gastrointestinal tissues from patients with active autoimmune complications of PI3Kδ inhibitors show infiltration with Th17 + T cells. These same tissues show depletion of Tregs as compared to CLL patients without toxicity, suggesting that loss of Tregs may be permissive for Th17 activation to lead to autoimmune toxicity. Clinical trials to restore this balance are warranted.

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Section: Impact Of Idelalisib and Duvelisib On T Cells In Vitrosupporting

confidence: 92%

Section: Introductionmentioning

confidence: 93%

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Circulating Th17 T Cells at Treatment Onset Predict Autoimmune Toxicity of PI3Kδ Inhibitors

Gadi

Martindale

Chiu

et al. 2022

Preprint

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“…As T cells also depend on PI3K signaling for differentiation and function ( 124 ), the effects of PI3K inhibitors on T cells have been investigated. CLL patients treated with idelalisib exhibit reduced Treg differentiation and function ( 113 , 114 ). Ex vivo treatment of CLL T cells with idelalisib disrupted Treg function, implying that PI3K inhibitors directly target Tregs ( 125 ).…”

Section: Impact Of Targeted Therapiesmentioning

confidence: 99%

Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

et al. 2022

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Regulatory T cells (Tregs) are responsible for maintaining immune homeostasis by controlling immune responses. They can be characterized by concomitant expression of FoxP3, CD25 and inhibitory receptors such as PD-1 and CTLA-4. Tregs are key players in preventing autoimmunity and are dysregulated in cancer, where they facilitate tumor immune escape. B-cell lymphoid malignancies are a group of diseases with heterogenous molecular characteristics and clinical course. Treg levels are increased in patients with B-cell lymphoid malignancies and correlate with clinical outcomes. In this review, we discuss studies investigating Treg immunobiology in B-cell lymphoid malignancies, focusing on clinical correlations, mechanisms of accumulation, phenotype, and function. Overarching trends suggest that Tregs can be induced directly by tumor cells and recruited to the tumor microenvironment where they suppress antitumor immunity to facilitate disease progression. Further, we highlight studies showing that Tregs can be modulated by novel therapeutic agents such as immune checkpoint blockade and targeted therapies. Treg disruption by novel therapeutics may beneficially restore immune competence but has been associated with occurrence of adverse events. Strategies to achieve balance between these two outcomes will be paramount in the future to improve therapeutic efficacy and safety.

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“…21 Toxicities mediated by idelalisib and duvelisib are thought to be immune mediated, and ex vivo or in vivo treatment with these agents affects regulatory T cell (Treg) functionality and numbers. [49][50][51][52] Interestingly, treatment of Eµ-TCL1 CLL mice with umbralisib was shown to spare the Tregs, as opposed to treatment with idelalisib or duvelisib, 53 suggesting a mechanism for the improved safety profile of umbralisib.…”

Section: Umbralisibmentioning

confidence: 99%

PI3K inhibitors in chronic lymphocytic leukemia: where do we go from here?

Skånland

Brown

2022

haematol

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Phosphatidylinositol 3-kinase (PI3K) inhibitors are effective in chronic lymphocytic leukemia (CLL). However, the severe toxicity profile associated with the first-generation inhibitors idelalisib and duvelisib, combined with the availability of other more tolerable agents, have limited their use. CLL is still considered incurable, and relapse after treatment, development of resistance, and treatment intolerance are common. It is therefore of interest to optimize the administration of currently approved PI3K inhibitors and to develop next-generation agents to improve tolerability, so that this class of agents will be considered an effective and safe treatment option when needed. These efforts are reflected in the large number of emerging clinical trials with PI3K inhibitors in CLL. Current strategies to overcome treatment limitations include intermittent dosing, which is established for copanlisib and zandelisib and under investigation for duvelisib and parsaclisib. A second strategy is to combine the PI3K inhibitor with another novel agent, either as a continuous regimen or a fixed-duration regimen, to deepen responses. In addition to these approaches, it is of interest to identify higher-resolution actionable biomarkers that can predict treatment responses and toxicity, and inform personalized treatment decisions. Here, we discuss the current status of PI3K inhibitors in CLL, factors limiting the use of currently approved PI3K inhibitors in CLL, current strategies to overcome these limitations, and where to go next.

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Idelalisib reduces regulatory T cells and activates T helper 17 cell differentiation in relapsed refractory patients with chronic lymphocytic leukaemia

Cited by 8 publications

References 15 publications

Circulating Th17 T Cells at Treatment Onset Predict Autoimmune Toxicity of PI3Kδ Inhibitors

Circulating Th17 T Cells at Treatment Onset Predict Autoimmune Toxicity of PI3Kδ Inhibitors

Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

PI3K inhibitors in chronic lymphocytic leukemia: where do we go from here?

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