PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients.

Chiara Tarantelli,Lisa Argnani,Francesco Bertoni,Pier Luigi Zinzani

doi:10.3390/cancers13215535

Abstract

Simple SummaryThis review focuses on the effects that a class of drugs, PI3Kδ inhibitors, used for the treatment of patients with lymphoma can have not on the neoplastic cells but on the normal cells and how this effect can modulate the immune response and potentially contribute to the anti-tumor response.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.

Highlights

Phosphoinositide 3-kinases (PI3Ks) are a class of enzymes fundamental in the regulation of cell metabolism, proliferation and survival [1,2,3,4,5,6]
Thheyeyeexxeertrtththeeirirssuupppprreessssiivvee mmeechanism by ddiiffffeerreennttmmooddaaliltiiteiess: :ddepeprirvivinigng IL-2 from the surrounding, reducing it for effector T-cells, by IL-2 binding with CD25; constitutively expressing Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), which down-regulates CD80/86 expression by antigen-presenting cells (APC) and limits co-stimulatory signals for Teff, together with CD28; immune-suppressive cytokines produced by Tregs decrease APC and Teff signals; Programmed Cell Death 1 (PD-1)/PD-L1 axis activation inhibits Teff function
While the effect of the PI3Kδ inhibitors on the secretion of chemokines has been studied in many clinical trials enrolling patients with lymphoma (Table 3), only a few studies have explored whether the drugs affect T-cell populations in the peripheral blood (Pb) [114,117,121,122,123] or in the tumor microenvironment (TME) [108,124]

Summary

Introduction

Phosphoinositide 3-kinases (PI3Ks) are a class of enzymes fundamental in the regulation of cell metabolism, proliferation and survival [1,2,3,4,5,6]. FDA, U.S Food and Drug Administration; target IC50 inhibition based on reported kinase inhibition profiles; #, based on http://adisinsight.springer.com/ and on https://clinicaltrials.gov accessed in 15 September 2021; ##, defined as “recruiting” or “not yet recruiting” in https://clinicaltrials.gov accessed in 15 September 2021; APDS/PASLI, Activated phosphoinositide 3-kinase delta syndrome/p110δ-activating mutation causing senescent T-cells, lymphadenopathy and immunodeficiency; CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; FL, follicular lymphoma; MZL, marginal zone lymphoma; ˆ, non in oncology; **, for the treatment of patients with (a) relapsed CLL in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities, (b) relapsed FL after at least two prior systemic therapies, (c) relapsed SLL after at least two prior systemic therapies) [46]; ***, for the treatment of adult patients with relapsed FL after at least two prior systemic therapies [47]; **** for the treatment of adult patients with (a) relapsed or refractory CLL/SLL after at least two prior therapies, (b) relapsed or refractory FL after at least two prior systemic therapies [48]; ***** for the treatment of adult patients with (a) relapsed or refractory MZL who have received at least one prior anti-CD20-based regimen and (b) for relapsed or refractory FL who have received at least three prior lines of systemic therapy [49]; inh., inhalation.; p.o., per os; i.v., intravenous

Immune System and Anti-Cancer Immunotherapy

Potential Toxicities Linked with PI3Kδ Inhibition in T-Cells

Effects on T-Cells in the Context of Clinical Trials

Conclusions