Erqian Yu (1), Sergey Smirnov (3), Xiaomin Song (2), Xiao Yang (2), Oleg Demin (3), Alexandra Diakonova (3), Galina Kolesova (3), Yan Ren (1)
(1) Clinical Pharmacology, BeiGene (Shanghai) Co., Ltd., Shanghai, China; (2) Preclinical Pharmacology, BeiGene (Beijing) Co., Ltd., Beijing, China; (3) InSysBio LLC, Moscow, Russia
Introduction
PI3Kδ is central to multiple signaling pathways that drive proliferation, survival, homing, and retention of malignant B-cells in lymphoid tissue and bone marrow[1]. It is also important for the homeostasis and function of T-regulatory cells[2]. PI3Kδ inhibitors are being developed for the treatment of hematologic malignancies and solid tumors[3,4]. The efficacy of PI3Kδ inhibitor monotherapy or combination treatment has been demonstrated in clinic[5-8], while the main concern in clinic safety is the severe colitis after long-term treatment[9]. Therefore, a QSP model was developed with the aim of exploring the relationship between the treatment of a new PI3Kδ inhibitor and its colitis occurrence risk.
Objectives
- To describe the signaling pathways connecting from PI3Kδ inhibition to the risk events of interest
- To predict the risk of colitis in the targeted patient population after being treated with a new PI3Kδ inhibitor
Methods
A minimal QSP model was built to integrate available preclinic/clinic data, literature knowledge, and scientific hypotheses about colitis development into a single biological framework. The sub-models describing life cycle of macrophages, dendritic cells, T cells, intestinal epithelial cells and neutrophils were adjusted to fit the project purposes. Two main types of cells were designated as drug targets: (1) regulatory T cells (Treg), (2) and effector T cells (Teff). PI3Kδ inhibitor has a stronger inhibition on Treg than Teff (IC50teff > IC50treg). It appears that Teff cells activation occurs at certain concentrations of the drug (depending on the ratio of IC50teff/IC50treg). Epithelial permeability, an indicator of colitis degree due to the good correlation with inflammation degree, was expressed as empiric function depending on IFNγ, IL-13 and TNFα. The drug concentrations in different compartments were assumed to be the same and equal to that in plasma.
A cohort of virtual patients (VPs) was generated by randomly varying certain model parameters, such as baseline permeability, IC50teff/IC50treg ratio, etc. These VPs were used to investigate the contribution of different model assumptions and parameters on epithelial permeability. Particular attention was paid to the contribution of intestinal inflammation (Th1- and Th2-mediated) types to the final effect, as well as to the mechanisms for increasing the severity of colitis with prolonged therapy.
Results
The minimal QSP model included five cell types, minimal set of cytokines participating in cell dynamics that regulate and responsible for colitis, the gut epithelium permeability, PK-PD, and the frequency/severity of colitis.
Simulations suggested that PI3Kδ inhibitor treatment can trigger a slowly developing inflammatory process. Th1 cells and macrophages are the main contributors to this process. For some VPs, inflammation may be self-sustained and non-resolving.
Simulations for VPs varying in the ratio of IC50teff/IC50treg showed a positive correlation exists between the degree of colitis severity and the ratio of IC50teff/IC50treg. There was no GI toxicity when the ratio of IC50teff/IC50treg equals to 1.
For the mechanisms behind GI toxicity, the simulations showed that PI3Kδ inhibitor may cause a dramatic increase in the concentration of IFNγ. Getting rid of IFNγ effector could offset the effect on permeability, while turning off all effectors had a similar effect. These results suggested that drug related colitis is Th1/IFNγ mediated.
The simulations also suggested that long-term treatment (>1 month) can increase the sensitivity of epithelial cells in some VPs, which may be caused by significant increase of Th1 cells and IFNγ. A slow (up to 3 years) increase in severity of colitis was associated with a slow increase in activity of macrophages 1 in lamina propria. There is a positive feedback between macrophages 1 and permeability.
Conclusions
PI3Kδ inhibitor triggers a slowly developing intestine inflammation. In some cases, the inflammatory process can be self-sustained and non-resolving. The drug related colitis is Th1/IFNγ mediated. A balance between the inhibition of PI3Kδ on Teff and Treg can play an essential role. Long-term treatment could increase the risk of colitis. The full QSP model will be further developed to capture more mechanisms of colitis pathways associated with PI3Kδ inhibitors, and to better predict the risk of colitis in the targeted patient population who are treated by a new PI3Kδ inhibitor.
References:
[1] Wei M, Wang X, Song Z, et al. Targeting PI3Kdelta: emerging therapy for chronic lymphocytic leukemia and beyond. Med Res Rev. 2015;35(4):720-52.
[2] Lim EL, Okkenhaug K. Phosphoinositide 3-kinase δ is a regulatory T-cell target in cancer immunotherapy. Immunology. 2019;157(3):210-218.
[3] Lucas CL, Chandra A, Nejentsev S, et al. PI3Kδ and primary immunodeficiencies. Nat Rev Immunol. 2016;16(11):702-714.
[4] Okkenhaug K, Burger JA. PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL). Curr Top Microbiol Immunol. 2016;393:123-142.
[5] Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. NEJM. 2014;370(11):997–1007.
[6] Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. NEJM. 2014;370(11):1008– 18.
[7] Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma. J Clin Oncol. 2019;37(11):912-22.
[8] Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: A multicenter, open label, registration directed phase II study. J Clin Oncol. 2019;37(15_suppl):7506
[9] Coutré, Steven E, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leukemia & Lymphoma, 2015:1-8.
Reference: PAGE () Abstr 9571 [www.page-meeting.org/?abstract=9571]
Poster: Drug/Disease Modelling - Oncology