Biology of Chronic Lymphocytic Leukemia in Different Microenvironments

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Key Points• In vivo PD-L1 blockade prevents CLL development in the Em-TCL1 adoptive transfer model. • In vivo PD-L1 blockade normalizes T-cell and myeloid cell populations and immune effector functions.Blockade of the programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint augments antitumor immunity and induces durable responses in patients with solid cancers, but data on clinical efficacy in leukemias are sparse. Chronic lymphocytic leukemia (CLL) is associated with a tumor-supportive microenvironment and a dysfunctional immune system, as shown by "exhausted" T cells, defective immunologic synapse formation, and immunosuppressive myeloid cells. These defects involve aberrant expression of PD-L1 and are closely mirrored in the Em-TCL1 mouse model for CLL. In this study, we treated mice after adoptive transfer of Em-TCL1 CLL with PD-L1-blocking antibodies, which prevented CLL development and was accompanied by a reactivation of immune effector functions. This included restoration of mature macrophages and major histocompatibility complex class II-expressing dendritic cells and prevention of aberrant and exhaustion-like T-cell phenotypes. In addition, PD-L1 blockade restored CD8 T-cell cytotoxicity and immune synapse formation and normalized T-cell cytokines and proliferation ex vivo and in vivo. Our data demonstrate that early PD-L1 blockade effectively corrects leukemia-induced immune dysfunction and thus prevents CLL development in mice. Targeting PD-L1/PD-1 interactions should therefore be further explored in clinical studies with CLL patients, ideally in combination with novel compounds to help eliminate CLL. (Blood. 2015;126(2):203-211)

Section: Pd-l1 Blockade Corrects Cll-induced Aberrant T-cell Phenotypsupporting

confidence: 79%

PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia

McClanahan

Hanna

Miller³

et al. 2015

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153

“…17 In CLL, activation of BCR signaling, particularly within the microenvironment of secondary lymphoid tissues, drives survival and proliferation of tumor cells. 18,19 Hence, there has been a growing interest in disrupting BCR signal transduction by targeting kinases downstream of the BCR. [20][21][22] Ibrutinib, which covalently binds and irreversibly inhibits Bruton tyrosine kinase (BTK), has demonstrated clinical efficacy in CLL as well as other B-cell malignancies and is approved for second-line treatment of CLL and mantle cell lymphoma, and for front-line treatment of CLL with deletion 17p13.1 and Waldenström macroglobulinemia.…”

Section: Introductionmentioning

confidence: 99%

Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib

Sun¹,

Tian

Lee³

et al. 2015

Self Cite

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165

• Ibrutinib allows for partial reconstitution of normal B cells and humoral immunity in patients with chronic lymphocytic leukemia.• Infection rate decreased with time on ibrutinib and was inversely correlated with improvements in serum IgA.Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P < .0001). To distinguish the effects on clonal B cells from normal B cells, we measured serum free light chains (FLCs). In k-clonal CLL cases, clonal (k) FLCs were elevated at baseline and normalized by 6 months. Nonclonal (l) FLCs, which were often depressed at baseline, increased, suggesting the recovery of normal B cells. Consistently, we observed normal B-cell precursors in the bone marrow and an increase in normal B-cell numbers in the peripheral blood. Patients with superior immune reconstitution, as defined by an increase in serum IgA of ‡50% from baseline to 12 months, had a significantly lower rate of infections (P 5 .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL.

“…In CLL, BCR signaling in the tumor cells is induced within the lymph node (LN) microenvironment. 23,24 However, the influence of the microenvironment on the pathogenesis of MCL has not been thoroughly investigated. 3 In ABC-DLBCL, chronic active BCR signaling has been linked to somatic mutations in CD79B.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma

Saba

Liu

Herman

et al. 2016

Self Cite

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