T‐cell CD38 expression in B‐chronic lymphocytic leukaemia

Abousamra, Nashwa K.; El-Din, Manal Salah; Azmy, Emad

doi:10.1002/hon.877

Cited by 7 publications

(5 citation statements)

References 36 publications

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“…CD38 expression on T cells has been shown to reflect chronic activation and stimulation in various diseases [32, 33] and also in acute graft rejection [34]. Our own group has recently shown that the levels of CD38 expression on T cells predict the course of the disease in male CLL patients with higher CD38 expression correlating with a worse clinical prognosis [35], and this was confirmed by the recent study by Abousamra et al [36]. According to these data, CD38 + T cells, despite their activated phenotype, seem to fail to perform sufficient tumour control in CLL but rather support maintenance or even expansion of the malignant clone.…”

Section: Discussionmentioning

confidence: 70%

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia

Gassner

Weiß

Geisberger

et al. 2010

Cancer Immunol Immunother

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The combination of cytotoxic treatment with strategies for immune activation represents an attractive strategy for tumour therapy. Following reduction of high tumour burden by effective cytotoxic agents, two major immune-stimulating approaches are being pursued. First, innate immunity can be activated by monoclonal antibodies triggering antibody-dependent cellular cytotoxicity. Second, tumour-specific T cell responses can be generated by immunization of patients with peptides derived from tumour antigens and infused in soluble form or loaded onto dendritic cells. The choice of cytotoxic agents for such combinatory regimens is crucial since most substances such as fludarabine are considered immunosuppressive while others such as cyclophosphamide can have immunostimulatory activity. We tested in this study whether fludarabine and/or cyclophosphamide, which represent a very effective treatment regimen for chronic lymphocytic leukaemia, would interfere with a therapeutic strategy of T cell activation. Analysis of peripheral blood samples from patients prior and during fludarabine/cyclophosphamide therapy revealed rapid and sustained reduction of tumour cells but also of CD4+ and CD8+ T cells. This correlated with a significant cytotoxic activity of fludarabine/cyclophosphamide on T cells in vitro. Unexpectedly, T cells surviving fludarabine/cyclophosphamide treatment in vitro had a more mature phenotype, while fludarabine-treated T cells were significantly more responsive to mitogenic stimulation than their untreated counterparts and showed a shift towards TH1 cytokine secretion. In conclusion, fludarabine/cyclophosphamide therapy though inducing significant and relevant T cell depletion seems to generate a micromilieu suitable for subsequent T cell activation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-010-0920-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 70%

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia

Gassner

Weiß

Geisberger

et al. 2010

Cancer Immunol Immunother

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“…9,16 Additionally, T-cell expression of CD38 has been shown to be important in a number of diseases, 41–43 such that imaging of this target in humanized mice 44 may provide insight into the behavior of T-cells and their homing to tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Preclinically, this PET tracer may find application in a wide variety of malignancies in which CD38 expression has been correlated with patient outcomes in order to better understand disease progression. , Additionally, T-cell expression of CD38 has been shown to be important in a number of diseases, − such that imaging of this target in humanized mice may provide insight into the behavior of T-cells and their homing to tumors.…”

Section: Discussionmentioning

confidence: 99%

CD38 as a PET Imaging Target in Lung Cancer

et al. 2017

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Daratumumab (Darzalex, Janssen Biotech) is a clinically approved antibody targeting CD38 for the treatment of multiple myeloma. However, CD38 is also expressed by other cancer cell types, including lung cancer, where its expression or absence may offer prognostic value. We therefore developed a PET tracer based upon daratumumab for tracking CD38 expression, utilizing murine models of non-small cell lung cancer to verify its specificity. Daratumumab was prepared for radiolabeling with 89Zr (t1/2 = 78.4 h) through conjugation with desferrioxamine (Df). Western blot, flow cytometry, and saturation binding assays were utilized to characterize CD38 expression and binding of daratumumab to three non-small cell lung cancer cell lines: A549, H460, and H358. Murine xenograft models of the cell lines were also generated for further in vivo studies. Longitudinal PET imaging was performed following injection of 89Zr-Df–daratumumab out to 120 h postinjection, and nonspecific uptake was also evaluated through the injection of a radiolabeled control IgG antibody in A549 mice, 89Zr-Df–IgG. Ex vivo biodistribution and histological analyses were also performed after the terminal imaging time point at 120 h postinjection. Through cellular studies, A549 cells were found to express higher levels of CD38 than the H460 or H358 cell lines. PET imaging and ex vivo biodistribution studies verified in vitro trends, with A549 tumor uptake peaking at 8.1 ± 1.2%ID/g at 120 h postinjection according to PET analysis, and H460 and H358 at lower levels at the same time point (6.7 ± 0.7%ID/g and 5.1 ± 0.4%ID/g, respectively; n = 3 or 4). Injection of a nonspecific radiolabeled IgG into A549 tumor-bearing mice also demonstrated lower tracer uptake of 4.4 ± 1.3%ID/g at 120 h. Immunofluorescent staining of tumor tissues showed higher staining levels present in A549 tissues over H460 and H358. Thus, 89Zr-Df–daratumumab is able to image CD38-expressing tissues in vivo using PET, as verified through the exploration of non-small cell lung cancer models in this study. This agent therefore holds potential to image CD38 in other malignancies and aid in patient stratification and elucidation of the biodistribution of CD38.

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“…It is therefore tempting to speculate that peculiar biological features of the residual T cell component in CLL, as it could be identified by the variable expression of specific markers, e.g. CD38, telomeres, CD25 and CD54 [41-45] or, as shown here, ZAP-70, might be the result of interactions of T cells themselves with CLL cells, which might eventually contribute to define the clinical features of the disease [40,46]. …”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of ZAP-70 expression in chronic lymphocytic leukemia: mean fluorescence intensity T/B ratio versus percentage of positive cells

et al. 2010

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BackgroundZAP-70 is an independent negative prognostic marker in chronic lymphocytic leukemia (CLL). Usually, its expression is investigated by flow cytometric protocols in which the percentage of ZAP-70 positive CLL cells is determined in respect to isotypic control (ISO-method) or residual ZAP-70 positive T cells (T-method). These methods, however, beside suffering of an inherent subjectivity in their application, may give discordant results in some cases. The aim of this study was to assess the prognostic significance of these methods in comparison with another in which ZAP-70 expression was evaluated as a Mean-Fluorescence-Intensity Ratio between gated T and CLL cells (T/B Ratio-method).MethodsCytometric files relative to ZAP-70 determination according to the three readouts were retrospectively reviewed on a cohort of 173 patients (test set), all with complete clinical and biological prognostic assessment and time-to-treatment (TTT) available. Findings were then validated in an independent cohort of 341 cases from a different institution (validation set).ResultsThe optimal prognostic cut-offs for ZAP-70 expression were selected at 11% (ISO-method) or 20% of positive cells (T-method), as well as at 3.0 (T/B Ratio-method) in the test set; these cut-offs yielded 66, 60 and 73 ZAP-70+ cases, respectively. Univariate analyses resulted in a better separation of ZAP-70+ vs. ZAP-70- CLL patients utilizing the T/B Ratio, compared to T- or ISO-methods. In multivariate analyses which included the major clinical and biological prognostic markers for CLL, the prognostic impact of ZAP-70 appeared stronger when the T/B-Ratio method was applied. These findings were confirmed in the validation set, in which ZAP-70 expression, evaluated by the T- (cut-off = 20%) or T/B Ratio- (cut-off = 3.0) methods, yielded 180 or 127 ZAP-70+ cases, respectively. ZAP-70+ patients according to the T/B Ratio-method had shorter TTT, both if compared to ZAP-70- CLL, and to cases classified ZAP-70+ by the T-method only.ConclusionsWe suggest to evaluate ZAP-70 expression in routine settings using the T/B Ratio-method, given the operator and laboratory independent feature of this approach. We propose the 3.0 T/B Ratio value as optimal cut-off to discriminate ZAP-70+ (T/B Ratio less than 3.0) from ZAP-70- (T/B Ratio more/equal than 3.0) cases.

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T‐cell CD38 expression in B‐chronic lymphocytic leukaemia

Cited by 7 publications

References 36 publications

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia

Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia

CD38 as a PET Imaging Target in Lung Cancer

Prognostic impact of ZAP-70 expression in chronic lymphocytic leukemia: mean fluorescence intensity T/B ratio versus percentage of positive cells

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