Autologous T-cell activation fosters ABT-199 resistance in chronic lymphocytic leukemia: rationale for a combined therapy with SYK inhibitors and anti-CD20 monoclonal antibodies

Elías, Esteban Enrique; Almejún, María Belén; Colado, Ana; Cordini, Gregorio; Vergara-Rubio, Maricef; Podaza, Enrique; Risnik, Denise; Cabrejo, María; Fernández-Grecco, Horacio; Bezares, Raimundo F.; Custidiano, Maria Del Rosario; Sánchez-Ávalos, Julio César; Vicente, Ascensión; Garate, Gonzalo; Borge, Mercedes; Giordano, Mirta; Gamberale, Romina

doi:10.3324/haematol.2018.188680

Cited by 14 publications

(24 citation statements)

References 15 publications

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“…5 a, b). Given that we have previously reported that venetoclax induces the apoptosis of T cells from CLL patients 14 , we also evaluated the effect of IVIg preparations on this cell population. Interestingly we found that IVIgGMA reduced T cell apoptosis induced by venetoclax while IVIgG did not (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Peripheral blood samples were obtained from CLL patients and peripheral blood mononuclear cells (PBMC) were isolated as previously described 14 .…”

Section: Methodsmentioning

confidence: 99%

“…Cell viability was also determined by flow cytometry by evaluating flow cytometric alteration of light scattering properties as previously described 14 , 27 . Briefly, apoptotic lymphocytes can be distinguished from viable lymphocytes by flow cytometry by their differences in cell morphology 28 .…”

Section: Methodsmentioning

confidence: 99%

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Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

Colado

Elías

Martínez

et al. 2021

Sci Rep

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Hypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

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Section: Resultsmentioning

confidence: 99%

“…Peripheral blood samples were obtained from CLL patients and peripheral blood mononuclear cells (PBMC) were isolated as previously described 14 .…”

Section: Methodsmentioning

confidence: 99%

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Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

Colado

Elías

Martínez

et al. 2021

Sci Rep

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“…Non-malignant lymphocytes (T + NK cells) were sensitive to venetoclax at 1 µM, but not when the drug was added at 0.1 µM (Figure 1C). Since it was previously reported that T cells from CLL patients and healthy donors are less sensitive to venetoclax (17,26), we compared the levels of cell death induced in HCL cells and in T + NK cells without finding a significant differential sensitivity to this drug in our experimental settings (Figure 1D).…”

Section: Venetoclax Induces Cell Death In Primary Hcl Leukemic Cellsmentioning

confidence: 99%

In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia

et al. 2021

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Current standard treatment of patients with hairy cell leukemia (HCL), a chronic B-cell neoplasia of low incidence that affects the elderly, is based on the administration of purine analogs such as cladribine. This chemotherapy approach shows satisfactory responses, but the disease relapses, often repeatedly. Venetoclax (ABT-199) is a Bcl-2 inhibitor currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) in adult patients ineligible for intensive chemotherapy. Given that HCL cells express Bcl-2, our aim was to evaluate venetoclax as a potential therapy for HCL. We found that clinically relevant concentrations of venetoclax (0.1 and 1 µM) induced primary HCL cell apoptosis in vitro as measured by flow cytometry using Annexin V staining. As microenvironment induces resistance to venetoclax in CLL, we also evaluated its effect in HCL by testing the following stimuli: activated T lymphocytes, stromal cells, TLR-9 agonist CpG, and TLR-2 agonist PAM3. We found decreased levels of venetoclax-induced cytotoxicity in HCL cells exposed for 48 h to any of these stimuli, suggesting that leukemic B cells from HCL patients are sensitive to venetoclax, but this sensitivity can be overcome by signals from the microenvironment. We propose that the combination of venetoclax with drugs that target the microenvironment might improve its efficacy in HCL.

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“…In other combinations, anti-CCR7 antibodies would mainly interfere with homing into LN and with the following interstitial migration within this tissue, whereas adjuvant therapies, such as the Bcl-2 inhibitor venetoclax, would collaborate in inducing cell death. Interestingly, venetoclax is markedly less toxic towards CLL cells when co-cultured with activated T lymphocytes ( 206 ) therefore, anti-CCR7 therapies could reverse this situation by impairing the support of CLL cells by accessory T cells. Finally, it is worth mentioning that un-mutated CLL clones are preferentially retained in LN, where they are exposed to proliferative stimuli, suggesting that anti-CCR7 strategies may be particularly effective in un-mutated-CLL.…”

Section: Ccr7 As a Novel Therapeutic Target In Cllmentioning

confidence: 99%

Of Lymph Nodes and CLL Cells: Deciphering the Role of CCR7 in the Pathogenesis of CLL and Understanding Its Potential as Therapeutic Target

Cuesta-Mateos

Brown

Terrón³

et al. 2021

Front. Immunol.

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The lymph node (LN) is an essential tissue for achieving effective immune responses but it is also critical in the pathogenesis of chronic lymphocytic leukemia (CLL). Within the multitude of signaling pathways aberrantly regulated in CLL the homeostatic axis composed by the chemokine receptor CCR7 and its ligands is the main driver for directing immune cells to home into the LN. In this literature review, we address the roles of CCR7 in the pathophysiology of CLL, and how this chemokine receptor is of critical importance to develop more rational and effective therapies for this malignancy.

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Autologous T-cell activation fosters ABT-199 resistance in chronic lymphocytic leukemia: rationale for a combined therapy with SYK inhibitors and anti-CD20 monoclonal antibodies

Abstract: . Autologous T cell activation fosters ABT-199 resistance in chronic lymphocytic leukemia: rationale for a combined therapy with SYK inhibitors and anti-CD20 MoAbs.

Cited by 14 publications

References 15 publications

Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia

Of Lymph Nodes and CLL Cells: Deciphering the Role of CCR7 in the Pathogenesis of CLL and Understanding Its Potential as Therapeutic Target

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