Innate PI3K p110δ Regulates Th1/Th17 Development and Microbiota-Dependent Colitis

Steinbach, Erin C.; Kobayashi, Taku; Russo, Steven M.; Sheikh, Shehzad Z.; Gipson, Gregory R.; Kennedy, Samantha T.; Uno, Jennifer K.; Mishima, Yoshiyuki; Borst, Luke B.; Liu, Bo; Herfarth, Hans H; Ting, Jenny P.Y.; Sartor, R. Balfour; Plevy, Scott E.

doi:10.4049/jimmunol.1301533

Cited by 51 publications

(55 citation statements)

References 43 publications

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“…Less frequent side effects, although probably drug-related, were pneumonitis, increased transaminases and diarrhoea . Idelalisib-induced colitis can be severe and a cause for drug discontinuation, as seen in clinical trials and murine models [Furman et al 2014;Steinbach et al 2014]. …”

Section: The Use Of Selective Pi3k Inhibitors In Cllmentioning

confidence: 99%

The biology behind PI3K inhibition in chronic lymphocytic leukaemia

Ortiz-Maldonado¹,

García-Morillo²,

Delgado³

2014

Therapeutic Advances in Hematology

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Phosphoinositide 3'-kinase (PI3K) is a key component of both chronic active and tonic B-cell receptor-signalling pathways. As such, PI3K inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukaemia. Multiple in vitro experiments and clinical trials have shown efficacy of these agents across all prognostic subgroups with a favourable toxicity profile. Moreover, in vitro studies suggest that combinations with monoclonal antibodies and/or other immune strategies could enhance the effect of PI3K inhibition.

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Section: The Use Of Selective Pi3k Inhibitors In Cllmentioning

confidence: 99%

The biology behind PI3K inhibition in chronic lymphocytic leukaemia

Ortiz-Maldonado¹,

García-Morillo²,

Delgado³

2014

Therapeutic Advances in Hematology

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“…Similar histological findings were noted in PI3Kδ knock-out mice that develop spontaneous colitis due to altered macrophage function resulting in a disturbed intestinal immune microenvironment. 92,93 These data suggest that colitis might be a class effect of PI3Kδ inhibitors. In fact, grade 3 or greater diarrhea is reported as an important side effect with other PI3Kδ inhibitors.…”

mentioning

confidence: 89%

The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia

Wiestner

2015

Haematologica

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Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic leukemia with B-cell receptor inhibitors, and summarizes the clinical experience with these agents. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia Adrian WiestnerHematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA ABSTRACT junction genes (J) in order to form a novel, unique sequence that encodes the antigen binding domain of the BCR (Figure 1). In theory, billions of different combinations are possible, generating a vastly diverse repertoire of possible antigen binding sites. However, CLL cells display a highly restricted, non-random repertoire of different immunoglobulin heavy chain variable (IGHV) region genes, suggesting that CLL cells have distinct antigen specificities. 15,18,19 Furthermore, the presence or absence of somatic mutations in the clonal IGHV gene, a mark of antigenic selection, distinguishes two major CLL subtypes; IGHV mutated (M-CLL) and IGHV unmutated (U-CLL); the latter having more than 98% sequence homology of the clonal IGHV g...

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“…p110δ is critical for Treg survival and function [15]. For example, p110δ-deficient mice develop an autoimmune colitis thought to be due to an impaired ability of Tregs to restrain inflammation in response to colonic microbiota [6, 16]. In sum, while the inhibition of p110δ does impair the function of conventional T cells, this is often counterbalanced by a decrease in Treg function.…”

Section: The Physiologic Role Of Pi3k Signaling In Hematopoietic Cmentioning

confidence: 99%

“…Toll-like receptor signaling in macrophages is enhanced with genetic p110δ inhibition [16]. Additionally, p110δ is required for dendritic cells to switch from a pro-inflammatory to anti-inflammatory state after exposure to lipopolysaccharide, and inhibition of p110δ leads to prolonged pro-inflammatory responses in dendritic cells [17].…”

Section: The Physiologic Role Of Pi3k Signaling In Hematopoietic Cmentioning

confidence: 99%

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Lampson

Brown

2017

Expert Opinion on Investigational Drugs

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Introduction Phosphatidylinositol-3-kinase (PI3K) inhibitors comprise a novel class of agents that are effective for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL). The demonstrated efficacy and subsequent FDA approval of the prototypical PI3Kδ inhibitor idelalisib has led to development of multiple compounds targeting this pathway. Areas Covered We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of tonic signaling from the B cell receptor, blockade of pro-survival signals from the microenvironment, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections and sepsis (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We then summarize PI3K inhibitors that have entered clinical trials for the treatment of lymphoma, focusing on agents with significant selectivity for PI3Kα and PI3Kδ. Expert Opinion PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, in comparison to other novel agents, idelalisib has infectious and autoimmune toxicities that have limited its use. Outside of clinical trials, the use of PI3K inhibitors should be restricted to CLL patients who have progressed on ibrutinib or iNHL patients who have progressed on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

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Innate PI3K p110δ Regulates Th1/Th17 Development and Microbiota-Dependent Colitis

Cited by 51 publications

References 43 publications

The biology behind PI3K inhibition in chronic lymphocytic leukaemia

The biology behind PI3K inhibition in chronic lymphocytic leukaemia

The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

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