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

Abstract

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.

p110δ PI3-Kinase Inhibition Perturbs APP and TNFα Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model

“…Because of its importance in immune signaling, PI3K␦ is considered an important therapeutic target in the treatment of inflammation and autoimmunity (Okkenhaug et al, 2002). Based on its high expression in leukocytes, it is also a target in hematological malignancies (Lampson and Brown, 2017), including chronic lymphocytic leukemia (Furman et al, 2014). Compared with leukocytes, PI3K␦ is also expressed at moderate levels in neurons (Eickholt et al, 2007;Low et al, 2014), and we demonstrate here that PI3K␦ inhibition blocks APP anterograde trafficking in hippocampal neurons.…”

PI3K alpha and delta promote hematopoietic stem cell activation

“…Our findings of the importance of the PI3K/AKT pathway in the HSC stress response also have important clinical implications. Several isoform-selective PI3K inhibitors are approved to treat lymphoid malignancies (39,40). For instance, idelalisib, which selectively targets p110δ, is used to treat chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma.…”

Germinal center‐derived lymphomas: The darkest side of humoral immunity

“…might lead to a situation highly advantageous for immune escape, but vulnerable to combination of metabolic and immunotherapies. 196,197 This could be due, at least in part, to the largely cytostatic effect of these drugs and to the cases mutational status not accounted for. Whether specific subtypes of DLBCL could particularly benefit from this treatment is currently unknown.…”

“…The PI3K pathway is implicated not only in lymphomas but almost every other cancer, leading to the development of many PI3K inhibitors with distinct isoform selectivity. Despite the pathway being altered, response rates in aggressive DLBCL as well as transformed FL were moderate for PI3K inhibitors 196,197. Despite the pathway being altered, response rates in aggressive DLBCL as well as transformed FL were moderate for PI3K inhibitors 196,197.…”