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, 11 (4), 184-6

Haematological Cancer: Idelalisib-Targeting PI3Kδ in Patients With B-cell Malignancies

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Haematological Cancer: Idelalisib-Targeting PI3Kδ in Patients With B-cell Malignancies

Jan A Burger et al. Nat Rev Clin Oncol.

Abstract

Idelalisib, the first PI3Kδ inhibitor in clinical use, has excellent activity in patients with chronic lymphocytic leukaemia and indolent B cell lymphomas, heralding a new era of targeted therapy for these types of cancer. Idelalisib intercepts critical communications between B cells and the microenvironment, including B cell receptor signalling and chemokine networks.

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Figure 1
Figure 1. Effects of idelalisib on cross talk between malignant B cells and the microenvironment
CLL cells and indolent non-Hodgkin’s lymphoma (iNHL) cells express B cell receptors (BCR) that are activated in the lymphoid tissues, leading to downstream signaling. PI3Kδ activation is a critical component of this signaling pathway, promoting survival and proliferation of the malignant cells (left). PI3Kδ activation also induces secretion of chemokines (CCL3, CCL4) by the malignant B cells, which in turn attract accessory cells, such as T cells, to the tissue microenvironment. These activation events are turned off by PI3Kδ blockade with idelalisib. In addition, idelalisib also interferes with tissue homing and retention mechanism (right hand side). Tissue stromal cells, such as monocyte-derived nurselike cells (NLC) and lymphoma-associated macrophages (LAM) secrete chemokines (CXCL12, CXCL13) which cause homing and tissue retention of CLL and iNHL cells. Blockade of chemokine receptor (CXCR4, CXCR5) signaling by idelalisib explains the re-distribution of tissue-resident CLL cells into the peripheral blood during idelalisib therapy.

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