scholarly journals The PI3K∂-Selective Inhibitor Idelalisib Induces T- and NK-Cell Dysfunction Independently of B-Cell Malignancy-Associated Immunosuppression

2021 ◽  
Vol 12 ◽  
Author(s):  
Lisa Rohrbacher ◽  
Bettina Brauchle ◽  
Ana Ogrinc Wagner ◽  
Michael von Bergwelt-Baildon ◽  
Veit L. Bücklein ◽  
...  
Keyword(s):  
B Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Selective Inhibitor ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Potential Contribution ◽  
B Cell Malignancy ◽  
Increased Risk ◽  
Cell Malignancy

B-cell receptors, multiple receptor tyrosine kinases, and downstream effectors are constitutively active in chronic lymphocytic leukemia (CLL) B cells. Activation of these pathways results in resistance to apoptosis and enhanced survival of the leukemic cells. Idelalisib is a highly selective inhibitor of the PI3K p110∂ isoform and is approved for the treatment of CLL in patients with relapsed/refractory disease or in those harboring 17p deletions or tp53 mutations. Despite the initial excitement centered around high response rates in clinical trials of idelalisib, its therapeutic success has been hindered by the incidence of severe opportunistic infections. To examine the potential contribution of idelalisib to the increased risk of infection, we investigated the effects of idelalisib on the immune cell compartments of healthy donors (HDs) and CLL patients. PI3K∂ blockade by idelalisib reduced the expression levels of inhibitory checkpoint molecules in T cells isolated from both HDs and CLL patients. In addition, the presence of idelalisib in cultures significantly decreased T-cell-mediated cytotoxicity and granzyme B secretion, as well as cytokine secretion levels in both cohorts. Furthermore, idelalisib reduced the proliferation and cytotoxicity of HD NK cells. Collectively, our data demonstrate that both human T and NK cells are highly sensitive to PI3K∂ inhibition. Idelalisib interfered with the functions of T and NK cell cells from both HDs and CLL patients. Therefore, idelalisib might contribute to an increased risk of infections regardless of the underlying B-cell malignancy.

scholarly journals PS1136 THE PI3KD-SELECTIVE INHIBITOR IDELALISIB INDUCES T AND NK CELL DYSFUNCTION INDEPENDENT OF B-CELL MALIGNANCY-ASSOCIATED IMMUNOSUPPRESION

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 514-515
Author(s):  
L. Rohrbacher ◽  
A. Ogrinc Wagner ◽  
A. Lohner ◽  
V. Bücklein ◽  
M. von Bergwelt-Baildon ◽  
...  
Keyword(s):  
B Cell ◽  
Nk Cell ◽  
Selective Inhibitor ◽  
Cell Dysfunction ◽  
B Cell Malignancy ◽  
Cell Malignancy

scholarly journals Therapeutic Targets in Chronic Lymphocytic Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3259
Author(s):  
Luca Laurenti ◽  
Dimitar G. Efremov
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Therapeutic Targets ◽  
Common Type ◽  
Lymphocytic Leukemia ◽  
Western Countries ◽  
B Cell Malignancy ◽  
Adult Leukemia ◽  
Cell Malignancy

Chronic lymphocytic leukemia (CLL) is a common B cell malignancy and is the most common type of adult leukemia in western countries [...]

scholarly journals Battle of Thermopylae: 300 Spartans (natural killer cells plus obinutuzumab) versus the immortal warriors (chronic lymphocytic leukemia cells) of Xerxes’ army

2019 ◽  
Vol 5 (10) ◽  
pp. FSO425
Author(s):  
Ricardo García-Muñoz ◽  
María-Josefa Nájera ◽  
Jesús Feliu ◽  
Judith Antón-Remírez ◽  
Enrique Ramalle-Gómara ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Killer Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Lymphokine Activated Killer Cells ◽  
Killer Cells

Aim: To analyze the effects of subcutaneous or intravenous rituximab + lymphokine-activated killer cells, obinutuzumab or ibrutinib on natural killer (NK) cell levels in chronic lymphocytic leukemia and follicular lymphoma patients. Patients & methods: The distribution of peripheral blood NK cells of 31 patients was analyzed by flow cytometry. Results: We detected a decrease of NK cells in peripheral blood below normal range after obinutuzumab treatment. During maintenance treatment with subcutaneous rituximab, an NK cell reduction was less pronounced than after intravenous rituximab treatment, despite lymphokine-activated killer cell infusions. Conclusion: After one dose of obinutuzumab, each NK cell in peripheral blood destroys 25 leukemic cells.

scholarly journals Patients with a deficiency of natural killer cell activity lack the VEP13-positive lymphocyte subpopulation

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 65-70 ◽  
Author(s):  
HW Ziegler-Heitbrock ◽  
H Rumpold ◽  
D Kraft ◽  
C Wagenpfeil ◽  
R Munker ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Target Cells ◽  
Nk Cell Activity

Many patients with B-type chronic lymphocytic leukemia (CLL) exhibit a profound defect in their natural killer (NK) cell activity, the basis of which is still obscure. Hence, we analyzed the NK cells from peripheral blood samples from 11 patients with CLL for phenotype and function, after removal of the leukemic cells with a monoclonal antibody (BA-1) plus complement. Phenotypic analysis of these nonleukemic cells with monoclonal antibodies (MoAbs) against NK cells revealed that the CLL patients had higher percentages of HNK-1-positive cells (23.5% compared to controls with 14.7%). In contrast, VEP13- positive cells were absent or low in seven patients (0.8% compared to controls with 11.2%) and normal in four patients (10.5%). When testing NK cell activities against K562 or MOLT 4 target cells, patients with no or minimal numbers of VEP13-positive cells were found to be deficient, while patients with normal percentages of VEP13-positive cells had NK cell activity comparable to controls. Isolation by fluorescence-activated cell sorter of HNK-1-positive cells from patients lacking VEP13-positive cells and NK cell activity indicated that the majority of the HNK-1-positive cells in these patients had the large granular lymphocyte morphology that is characteristic of NK cells. Thus, the deficiency of NK cell activity in CLL patients appears to result from the absence of cells carrying the VEP13 marker.

Monoclonal Gammopathy (MG) Associated with Gaucher Disease (GD). Report of 16 Cases from the French Observatoire on Gaucher Disease (FROG Study).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5004-5004
Author(s):  
Bernard Grosbois ◽  
Jean Leone ◽  
Fabrice Camou ◽  
Florence Dalbies ◽  
Jean Robert Harle ◽  
...  
Keyword(s):  
General Population ◽  
B Cell ◽  
Gaucher Disease ◽  
Bone Marrow Aspiration ◽  
Lymphocytic Leukemia ◽  
Imaging Data ◽  
Enzyme Replacement ◽  
Non Hodgkin Lymphoma ◽  
B Cell Malignancy ◽  
Cell Malignancy

Abstract In addition to its common bone and visceral manifestations GD is frequently associated with B cell proliferation leading possibly to MG. The objective of our study was to determine the frequency and presentation of MG in GD patients. Material and methods. FROG is a cross-sectionnal epidemiological study on adult GD involving 64 French centers. Standard clinical, biological(including serum protein electrophoresis) and imaging data performed as part of usual management within the 3 previous years were collected at the time of a routine visit. In patients with suspected MG specific additionnal data were studied:immunofixation, dosage of immunoglobulins, bone marrow aspiration. Results. From 05/2005 to 06/2006 seventy seven adult GD type 1(38 male,39 female;mean age 47.3 years, range 18 to 78 years) were included. Sixteen cases of MG(20.8%) were observed (10 male and 6 female;mean age 61.25 years, range 47 to 79 years). Mean age of 61 cases of GD without MG(43.8 years;range 18 to 70 years)was significantly lower(p<0.0001). Thirteen cases(17%)were classified as MGUS and 3 (3.8%) as B cell malignancy:1 multiple myeloma, 1 Chronic Lymphocytic Leukemia, 1 Non Hodgkin Lymphoma. In 3 cases MG and GD were diagnosed simultaneously. In 13 cases MG was diagnosed in the course of GD(mean interval 12.2 years;range 6.7 to 16 years). MG immunochemical typing revealed 75 % Ig G, 12.5 %Ig A, 12.5 %Ig M, 75 % Kappa and 25 % Lambda. We observed one biclonal gammopathy(IgG and IgA Kappa). One case of MGUS was associated with capillary leak syndrome. In two patients MG level decreased with enzyme replacement therapy. Conclusion. Frequency of MG in GD observed in our study (20.8%)is largely higher than in general population (1%). Furthermore this frequency is higher than in previous series of GD. However in GD patients, as observed in general population, frequency of MG seems to be related to age as mean age of patients with MG is significantly higher than mean age of patients without MG. Finally these data assess the need of specific follow-up regarding the high frequency of MG and the risk of B cell malignancy in GD patients.

Pre-Clinical Activity of a Novel FcγRIIIa Engineered CD19 Monoclonal Antibody in B Cell Chronic Lymphocytic Leukemia and Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2351-2351
Author(s):  
Julie M. Roda ◽  
Rosa Lapalombella ◽  
Robert Baiocchi ◽  
Eugene Zhukocsky ◽  
John Desjarlais ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Negative Control ◽  
Lymphocytic Leukemia ◽  
Adcc Activity ◽  
Specific Lysis

Abstract CD19 is a B cell lineage-specific transmembrane signaling protein that controls differentiation and proliferation. CD19 is an attractive therapeutic target due to its high level of expression in numerous B cell malignancies, as well as its lack of expression on non-B cells. Here we report the in vitro anti-tumor activity of a novel humanized monoclonal anti-CD19 Ab (CD19-IgG1, aka XENP5603) and its Fc engineered counterpart (XmAb™CD19, aka XENP5574). XENP5603 induced direct apoptosis in normal CD19+ B cells, but not NK cells, T cells, or monocytes, as determined by flow cytometric staining with annexin V and propidium iodide. XENP5603 also induced significant levels of apoptosis in a number of lymphoblastoid cell lines, including Ramos, Raji, 697, NALM6, and RS4;11 cells. Treatment of primary chronic lymphocytic leukemia (CLL) cells with XENP5603 induced significant cell death in all patients tested (mean, 36% apoptotic cells at 24 hours; range, 13–66%, p < 0.001). Similar apoptosis was noted in cells from a subset of patients (4 of 9) with CD19+ primary acute lymphoblastic leukemia (ALL). Apoptosis of CLL cells treated with XENP5603 was not associated with cleavage of caspase-3, caspase-8, caspase-9, or PARP, but was associated with upregulation of Bim, suggesting a caspase-independent mechanism of cell death. NK cells from normal donors exhibited high levels of ADCC in response to B cell lines coated with XENP5603. Furthermore, NK cells from CLL patients mediated significant ADCC against autologous CLL cells in the presence of XENP5603 (mean, 15% specific lysis at an E:T ratio of 25:1; range, 8–24%; p = 0.04 vs. the negative control Ab). ADCC activity was further increased in the presence of XENP5574, which has the same antigen-recognition sequences as XENP5603 but which contains two mutations in the Fc region that increase FcγRIIIa affinity (mean, 39% specific lysis at an E:T ratio of 25:1; range, 29–51%; p = 0.02 vs. the negative control Ab). ADCC mediated by either CD19 Ab was also significantly higher than that mediated by an equivalent concentration of rituximab (mean, 39% specific lysis with XENP5574 vs. 12% with rituximab; p < 0.001). ADCC in the presence of either Ab was further increased in the presence of the NK cell-activating cytokine IL-2, suggesting that these antibodies might be effectively combined with immune stimulatory adjuvants. Furthermore, NK cell ADCC against CLL cells in the presence of CD19 Abs was found to be dependent on perforin/granzyme release, as treatment with 3,4-dichloroisocoumarin (which inhibits granzyme enzymatic activity) or EGTA (which prevents release of cytotoxic vesicles) potently inhibited ADCC activity. Collectively, these studies provide evidence of the autologous innate immune-mediated cytotoxicity and direct apoptotic activity of XENP5603 and XENP5574. In addition, engineering to enhance FcγRIIIa binding enhances autologous ADCC, providing support for further pre-clinical development of XENP5574 in CD19+ malignancies, including CLL and ALL.

scholarly journals The most frequent t(14;19)(q32;q13)-positive B-cell malignancy corresponds to an aggressive subgroup of atypical chronic lymphocytic leukemia

Leukemia ◽  
2008 ◽  
Vol 22 (11) ◽  
pp. 2123-2127 ◽  
Author(s):  
E Chapiro ◽  
◽  
I Radford-Weiss ◽  
C Bastard ◽  
I Luquet ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancy ◽  
Cell Malignancy

scholarly journals Patients with a deficiency of natural killer cell activity lack the VEP13-positive lymphocyte subpopulation

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 65-70 ◽  
Author(s):  
HW Ziegler-Heitbrock ◽  
H Rumpold ◽  
D Kraft ◽  
C Wagenpfeil ◽  
R Munker ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Target Cells ◽  
Nk Cell Activity

Abstract Many patients with B-type chronic lymphocytic leukemia (CLL) exhibit a profound defect in their natural killer (NK) cell activity, the basis of which is still obscure. Hence, we analyzed the NK cells from peripheral blood samples from 11 patients with CLL for phenotype and function, after removal of the leukemic cells with a monoclonal antibody (BA-1) plus complement. Phenotypic analysis of these nonleukemic cells with monoclonal antibodies (MoAbs) against NK cells revealed that the CLL patients had higher percentages of HNK-1-positive cells (23.5% compared to controls with 14.7%). In contrast, VEP13- positive cells were absent or low in seven patients (0.8% compared to controls with 11.2%) and normal in four patients (10.5%). When testing NK cell activities against K562 or MOLT 4 target cells, patients with no or minimal numbers of VEP13-positive cells were found to be deficient, while patients with normal percentages of VEP13-positive cells had NK cell activity comparable to controls. Isolation by fluorescence-activated cell sorter of HNK-1-positive cells from patients lacking VEP13-positive cells and NK cell activity indicated that the majority of the HNK-1-positive cells in these patients had the large granular lymphocyte morphology that is characteristic of NK cells. Thus, the deficiency of NK cell activity in CLL patients appears to result from the absence of cells carrying the VEP13 marker.

scholarly journals BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1766
Author(s):  
Christian Sordo-Bahamonde ◽  
Seila Lorenzo-Herrero ◽  
Ana P Gonzalez-Rodriguez ◽  
Ángel R. Payer ◽  
Esther González-García ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Nk Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
In Silico Analysis ◽  
Immune Checkpoint Blockade ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Poor Outcome

Chronic lymphocytic leukemia (CLL) is characterized by progressive immunosuppression and diminished cancer immunosurveillance. Immune checkpoint blockade (ICB)-based therapies, a major breakthrough against cancer, have emerged as a powerful tool to reinvigorate antitumor responses. Herein, we analyzed the role of the novel inhibitory checkpoint BTLA and its ligand, HVEM, in the regulation of leukemic and natural killer (NK) cells in CLL. Flow cytometry analyses showed that BTLA expression is upregulated on leukemic cells and NK cells from patients with CLL, whereas HVEM is downregulated only in leukemic cells, especially in patients with advanced Rai-Binet stage. In silico analysis revealed that increased HVEM, but not BTLA, mRNA expression in leukemic cells correlated with diminished overall survival. Further, soluble BTLA (sBTLA) was found to be increased in the sera of patients with CLL and highly correlated with poor prognostic markers and shorter time to treatment. BTLA blockade with an anti-BTLA monoclonal antibody depleted leukemic cells and boosted NK cell-mediated responses ex vivo by increasing their IFN-γ production, cytotoxic capability, and antibody-dependent cytotoxicity (ADCC). In agreement with an inhibitory role of BTLA in NK cells, surface BTLA expression on NK cells was associated with poor outcome in patients with CLL. Overall, this study is the first to bring to light a role of BTLA/HVEM in the suppression of NK cell-mediated immune responses in CLL and its impact on patient’s prognosis, suggesting that BTLA/HVEM axis may be a potential therapeutic target in this disease.

Sign in / Sign up

Export Citation Format

Share Document