Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL

Christopoulos, Petros; Pfeifer, Dietmar; Bartholomé, Kilian; Follo, Marie; Timmer, Jens; Fisch, Paul; Veelken, Hendrik

doi:10.1182/blood-2010-07-299321

Cited by 99 publications

(105 citation statements)

References 49 publications

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“…16,19,[22][23][24][25] The precise role that different T-cell subsets play in the immunodeficiency of CLL remains undetermined but functional studies have identified defects in immune synapse formation, costimulatory/accessory molecule expression and cytokine release. [15][16][17] Despite these problems, several T-cell-based therapeutic strategies have been tried in CLL including adoptive transfer of anti-CD3/anti-CD28 activated T cells, 26 T cells expressing chimeric antigen receptors, and vaccine therapy with dendritic cells pulsed with CLL-cell lysates. [27][28][29] The potential power of T cells to mediate therapeutic responses in CLL was demonstrated in a recent study using adoptive transfer of gene-modified (CD19 chimeric antigen receptor and 4-1BB) T cells.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 However, given the well-known T-cell dysfunction seen in CLL, blinatumomab may be less effective in this disease. [15][16][17] In the current study, we provide a detailed analysis of the mechanism of action of blinatumomab-induced cytotoxicity in CLL. Our findings are consistent with a model that relies upon the sequential activation of T cells and CLL cells and demonstrate that blinatumomab retains efficacy even in the presence ©2013 Ferrata Storti Foundation.…”

Section: Cd23mentioning

confidence: 99%

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Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o n 2 0 1 3of CLL activation and pro-survival signals. Given these data, this approach represents a novel and promising therapeutic strategy for the treatment of CLL and, potentially, other lymphoid malignancies. Methods Blood samples from patients with chronic lymphocytic leukemiaTwenty-eight CLL patients (aged 53-83 years) were studied with full ethical approval. All blood samples from patients were obtained with informed consent (see Online Supplementary Methods). The majority of the assays were performed on fresh samples from treatment-naïve patients, except those for which the results are shown in Figure 1: in these assays, samples from patients who had received standard chemotherapy treatment were also tested. Antibodies and flow cytometryA full list of the antibodies used can be found in the Online Supplementary Methods. Blinatumomab (MT103, AMG103) was provided by Amgen Inc. (Munich, Germany). T cells were identified using CD4 and CD8 markers, while CLL cells were CD5 + CD4-CD8 -(>99% CD19 + ). Cell culturesPeripheral blood mononuclear cells (PBMC) were incubated in RPMI 1640 supplemented with 5% AB serum (AB media) for 3-7 days. Blinatumomab was added to PBMC cultures at a concentration of 10 or 100 ng/mL. Human T-cell activator CD3/CD28 dynabeads (Invitrogen) were added at 1x10 5 beads/1x10 6 PBMC as a positive control for T-cell activation. For absolute counts of T cells and CLL cells, an anti-CD3 antibody (Invitrogen) at a dose of 27.7 or 277 ng/mL was used as a positive control (same molar concentration as 10 or 100 ng/mL blinatumomab). Intracellular Ki67 stainingPBMC were labeled with antibodies against CD4, CD8, CCR7 and CD45RA, fixed and permeabilized (Fix and Perm with 1% NP40, Caltag-Medsystems, Buckingham, UK) before staining with a Ki67-FITC antibody for flow cytometric analysis. Cytokine secretion assayCytokines in tissue culture supernatants were measured using a Human Th1/Th2 11plex RTU Flowcytomix kit (eBioscience) for simultaneous detection of 11 cytokines. Intracellular cytokine staining and the determination of CD107 and granzyme B expressionPBMC were cultured (3 days) with 10 ng/mL blinatumomab, before treatment with Golgi plug and Golgi stop (BD biosciences), and incubation with an anti-CD107 antibody (5 h at 37°C). Intracellular expression of granzyme B or interferon (IFN)-g and tumor necrosis factor (TNF)-α in CD4 or CD8 T cells was measured by flow cytometry. Absolute counts of T cells and chronic lymphocytic leukemia cellsPBMC samples that had or had not been treated with blinatumomab (7 days) were surface-stained with antibodies against annexin V, CD5, CD8 and CD4. Absolute counts were determined by flow cytometry using Cytocount beads (Dako, Stockport, UK). Flow cytometry-based cytotoxicity assayMouse fibroblast cells transfected with CD40L [TL(CD40L)] and non-transfected cells (NTL) were cultured as previously described. 21 For co-cultures, irradiated (80 Gy) NTL or TL(CD40L) cells were seeded into a 48-well plate, and allow...

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Section: Discussionmentioning

confidence: 99%

Section: Cd23mentioning

confidence: 99%

Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells

et al. 2013

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“…B cell CLL (B-CLL) patients have a T cell subpopulation with lower levels of CD4 or CD8 than classical T lymphocytes. This may result from a nonclassical T cell developmental pathway or B cell interaction (12)(13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

Secondary primary malignancy presence and related factors in chronic lymphocytic leukemia

Ekinci

Doğan

Demi̇rci̇oğlu

et al. 2018

Medical Science and Discovery

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“…While responses in CLL are impressive we note that they do not approach the dramatic 70%-90% CR rates observed in ALL. Reasons for this may be due to functional defects in CLL patients' T-cells with resulting differences in the functionality and composition of the manufactured T-cell product or differences in engagement with cancer cells due to the CLL tumor microenvironment [15,35,36]. To date, in CLL we have not been able to identify baseline patient or disease defining characteristics that differentiate responders from non-responders [6].…”

Section: Clinical Outcomes Of Cd19-car T-cell Therapymentioning

confidence: 99%

CART‐cells merge into the fast lane of cancer care

Frey

Porter

2015

American J Hematol

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Chimeric antigen receptors (CARs) can be introduced into T-cells redirecting them to target specific tumor antigens. CAR-modified T cells targeting CD19 have shown remarkable activity against CD191 malignancies including B cell acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphomas (NHL). Complete remission rates as high as 90% have been observed for patients with relapsed and refractory ALL and greater than 50% response rates have been seen in heavily pre-treated CLL and NHL. Excitingly, some remissions have been durable without any additional therapy, a finding which correlates with in-vivo T-cell persistence and B-cell aplasia. The major treatment related toxicities include Bcell aplasia, neurologic toxicities, and a potentially severe cytokine release syndrome. This review summarizes outcomes for patients treated with CD19-CAR T-cells while exploring the field's challenges and future directions.

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Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL

Cited by 99 publications

References 49 publications

Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells

Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells

Secondary primary malignancy presence and related factors in chronic lymphocytic leukemia

CART‐cells merge into the fast lane of cancer care

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