PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients

Abstract

The development of small molecules able to block specific or multiple isoforms of phosphoinositide 3-kinases (PI3K) has already been an active field of research for many years in the cancer field. PI3Kδ inhibitors are among the targeted agents most extensively studied for the treatment of lymphoma patients and PI3Kδ inhibitors are already approved by regulatory agencies. More recently, it became clear that the anti-tumor activity of PI3K inhibitors might not be due only to a direct effect on the cancer cells but it can also be mediated via inhibition of the kinases in non-neoplastic cells present in the tumor microenvironment. T-cells represent an important component of the tumor microenvironment and they comprise different subpopulations that can have both anti- and pro-tumor effects. In this review article, we discuss the effects that PI3Kδ inhibitors exert on the immune system with a particular focus on the T-cell compartment.

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

“…PI3K inhibitors targeting one or more class I catalytic subunits (p110α, β, γ, δ) abrogate pro-survival signaling in B cells. Several PI3K inhibitors have been approved for use in B-NHL patients including idelalisib (targeting δ), duvelisib (targeting δ/γ) and copanlisib (targeting α/δ) ( 123 ). As T cells also depend on PI3K signaling for differentiation and function ( 124 ), the effects of PI3K inhibitors on T cells have been investigated.…”

Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis

“…1,2 Indeed, its inhibition is being extensively explored as a therapeutic approach for patients with lymphoid neoplasms. [1][2][3] Idelalisib was the first-in-class specific PI3Kδ inhibitor to show clinical activity as a single agent in patients with follicular lymphoma, marginal zone lymphoma (MZL), chronic lymphocytic leukemia and mantle cell lymphoma, and in combination with rituximab in patients with chronic lymphocytic leukemia, 1,2 and it received the approval from the U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed follicular lymphoma or small lymphocytic lymphoma after at least two prior systemic therapies, and, in combination with rituximab, for patients with relapsed chronic lymphocytic leukemia. 3 Idelalisib has been successfully followed by a series of second-generation PI3Kδ inhibitors, such as parsaclisib and zandelisib, and by compounds that inhibit additional kinases, such as copanlisib (PI3Kα/PI3Kδ), duvelisib (PI3Kδ/PI3Kg) and umbralisib (PI3Kδ and casein kinase-1ε), achieving clinical responses in lymphomas, including follicular lymphoma, mantle cell lymphoma, MZL and chronic lymphocytic leukemia.…”

“…[1][2][3] Idelalisib was the first-in-class specific PI3Kδ inhibitor to show clinical activity as a single agent in patients with follicular lymphoma, marginal zone lymphoma (MZL), chronic lymphocytic leukemia and mantle cell lymphoma, and in combination with rituximab in patients with chronic lymphocytic leukemia, 1,2 and it received the approval from the U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed follicular lymphoma or small lymphocytic lymphoma after at least two prior systemic therapies, and, in combination with rituximab, for patients with relapsed chronic lymphocytic leukemia. 3 Idelalisib has been successfully followed by a series of second-generation PI3Kδ inhibitors, such as parsaclisib and zandelisib, and by compounds that inhibit additional kinases, such as copanlisib (PI3Kα/PI3Kδ), duvelisib (PI3Kδ/PI3Kg) and umbralisib (PI3Kδ and casein kinase-1ε), achieving clinical responses in lymphomas, including follicular lymphoma, mantle cell lymphoma, MZL and chronic lymphocytic leukemia. [1][2][3] In particular, data have so far led to the FDA approval of copanlisib for patients with relapsed/refractory follicular lymphoma, duvelisib for patients with relapsed/refractory chronic lymphocytic leukemia, small lymphocytic lymphoma or follicular lymphoma, and umbralisib for the treatment of patients with relapsed/refractory MZL or follicular lymphoma.…”

“…3 Idelalisib has been successfully followed by a series of second-generation PI3Kδ inhibitors, such as parsaclisib and zandelisib, and by compounds that inhibit additional kinases, such as copanlisib (PI3Kα/PI3Kδ), duvelisib (PI3Kδ/PI3Kg) and umbralisib (PI3Kδ and casein kinase-1ε), achieving clinical responses in lymphomas, including follicular lymphoma, mantle cell lymphoma, MZL and chronic lymphocytic leukemia. [1][2][3] In particular, data have so far led to the FDA approval of copanlisib for patients with relapsed/refractory follicular lymphoma, duvelisib for patients with relapsed/refractory chronic lymphocytic leukemia, small lymphocytic lymphoma or follicular lymphoma, and umbralisib for the treatment of patients with relapsed/refractory MZL or follicular lymphoma. 3 The identification of the mechanisms underlying either primary or secondary resistance to PI3Kδ inhibitors is fundamental to optimize the use of these drugs, and a number of studies have described mechanisms of resistance to this class of agents in lymphoid neoplasms, driven by activation of alternative signaling cascades.…”

“…[1][2][3] In particular, data have so far led to the FDA approval of copanlisib for patients with relapsed/refractory follicular lymphoma, duvelisib for patients with relapsed/refractory chronic lymphocytic leukemia, small lymphocytic lymphoma or follicular lymphoma, and umbralisib for the treatment of patients with relapsed/refractory MZL or follicular lymphoma. 3 The identification of the mechanisms underlying either primary or secondary resistance to PI3Kδ inhibitors is fundamental to optimize the use of these drugs, and a number of studies have described mechanisms of resistance to this class of agents in lymphoid neoplasms, driven by activation of alternative signaling cascades. [4][5][6][7][8][9][10][11] Here we present a model of secondary resistance to PI3Kδ inhibitors, including duvelisib, copanlisib and umbralisib, obtained by prolonged exposure of a splenic MZL cell line to idelalisib.…”