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  • 1
    Online Resource
    Online Resource
    Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. 1 ( 2019-07-04), p. 44-58
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. 1 ( 2019-07-04), p. 44-58
    Abstract: In chronic lymphocytic leukemia (CLL), acquired T-cell dysfunction impedes development of effective immunotherapeutic strategies, through as-yet unresolved mechanisms. We have previously shown that CD8+ T cells in CLL exhibit impaired activation and reduced glucose uptake after stimulation. CD8+ T cells in CLL patients are chronically exposed to leukemic B cells, which potentially impacts metabolic homeostasis resulting in aberrant metabolic reprogramming upon stimulation. Here, we report that resting CD8+ T cells in CLL have reduced intracellular glucose transporter 1 (GLUT1) reserves, and have an altered mitochondrial metabolic profile as displayed by increased mitochondrial respiration, membrane potential, and levels of reactive oxygen species. This coincided with decreased levels of peroxisome proliferator-activated receptor γ coactivator 1-α, and in line with that, CLL-derived CD8+ T cells showed impaired mitochondrial biogenesis upon stimulation. In search of a therapeutic correlate of these findings, we analyzed mitochondrial biogenesis in CD19-directed chimeric antigen receptor (CAR) CD8+ T cells prior to infusion in CLL patients (who were enrolled in NCT01747486 and NCT01029366 [https://clinicaltrials.gov]). Interestingly, in cases with a subsequent complete response, the infused CD8+ CAR T cells had increased mitochondrial mass compared with nonresponders, which positively correlated with the expansion and persistence of CAR T cells. Our findings demonstrate that GLUT1 reserves and mitochondrial fitness of CD8+ T cells are impaired in CLL. Therefore, boosting mitochondrial biogenesis in CAR T cells might improve the efficacy of CAR T-cell therapy and other emerging cellular immunotherapies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2018885863
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    Online Resource
    Online Resource
    The Broad Kinase Inhibitor Dasatinib in Combination with Fludarabine in Patients with Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase 2 Study
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1798-1798
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1798-1798
    Abstract: Abstract 1798 Introduction Development of chemoresistance in chronic lymphocytic leukemia (CLL) is at least partly mediated by protective stimuli within the lymph node (LN) microenvironment. Dasatinib has activity against multiple kinases which have been reported to be activated by the microenvironment, including SRC, c-Abl and BTK. We have recently shown that Dasatinib can effectively inhibit the anti-apoptotic program and as a consequence, restore fludarabine sensitivity in vitro. Patients and methods We conducted an open-label phase 2 trial of Dasatinib combined with fludarabine in twenty refractory CLL patients. Patients were treated with Dasatinib 100 mg once daily for 28 days. In patients who did not reach at least a PR, fludarabine was added (40 mg/m2 for 3 consecutive days q28) for at least 2 and a maximum of 6 cycles. Response assessments included CT-scans at baseline, following 4 weeks of Dasatinib monotherapy, after 2 cycles of combination therapy and at the end of protocol. In a subset of patients with high numbers of circulating lymphocytes at baseline, RNA expression profiles of apoptosis regulator genes as well as inflammation genes were analyzed prior and during treatment by MLPA analysis. Results Toxicities were comparable to those observed in fludarabine containing regimens and as expected in heavily pre-treated refractory patients. Three patients (18%) reached a PR. Although most patients did not reach a formal nodal response, most patients showed reduction in lymph node (LN) size with a median of −20% as best response. Subsequent dasatinib fludarabine treatment following dasatinib monotherapy induced additional clinical effects but primarily in patients without del11q or del17p. Patients with a LN reduction of at least 20% had a significant improved PFS (256 days) and OS (510 days) as compared to non-responders (80 days and 158 days respectively). Also, in responding patients PFS was superior to PFS after last prior treatment. NF-κB expression levels decreased while expression levels of the pro-apoptotic gene NOXA increased both after Dasatinib treatment and combination treatment. Conclusion In conclusion, Dasatinib fludarabine combination treatment has clinical efficacy in heavily pretreated refractory patients which correlated with decreased NF-κB and increased NOXA expression. As recently showed with other targeted agents, improvement of PFS and OS is also observed in patients with tumor responses less than 50%. These data do encourage further studies on a broad-spectrum kinase inhibitor like Dasatinib in combination with other classes of drugs in relapsed and refractory CLL. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1798.1798
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    CMV-specific CD8+ T-cell function is not impaired in chronic lymphocytic leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 123, No. 5 ( 2014-01-30), p. 717-724
    Details
    In: Blood, American Society of Hematology, Vol. 123, No. 5 ( 2014-01-30), p. 717-724
    Abstract: Expression of exhaustion markers is decreased on CMV-specific CD8+ T cells from CLL patients as compared with those from age-matched HCs. Functionality of CMV-specific CD8+ T cells in CLL with respect to cytokine production, cytotoxicity, and immune synapse formation is preserved.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2013-08-518183
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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