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  1. Article ; Online: Inappropriate Expression of PD-1 and CTLA-4 Checkpoints in Myeloma Patients Is More Pronounced at Diagnosis

    Anna Kulikowska de Nałęcz / Lidia Ciszak / Lidia Usnarska-Zubkiewicz / Edyta Pawlak / Irena Frydecka / Magdalena Szmyrka / Agata Kosmaczewska

    International Journal of Molecular Sciences, Vol 24, Iss 5730, p

    Implications for Time to Progression and Response to Therapeutic Checkpoint Inhibitors

    2023  Volume 5730

    Abstract: Multiple myeloma (MM) is a hematologic malignancy characterized by severely profound immune dysfunction. Therefore, the efficacy of drugs targeting the immune environments, such as immune checkpoint inhibitors (ICIs), is of high clinical importance. ... ...

    Abstract Multiple myeloma (MM) is a hematologic malignancy characterized by severely profound immune dysfunction. Therefore, the efficacy of drugs targeting the immune environments, such as immune checkpoint inhibitors (ICIs), is of high clinical importance. However, several clinical trials evaluating ICIs in MM in different therapeutic combinations revealed underwhelming results showing a lack of clinical efficacy and excessive side effects. The underlying mechanisms of resistance to ICIs observed in the majority of MM patients are still under investigation. Recently, we demonstrated that inappropriate expression of PD-1 and CTLA-4 on CD4 T cells in active MM is associated with adverse clinical outcomes and treatment status. The aim of the current study was to determine the usefulness of immune checkpoint expression assessment as a predictive biomarker of the response to therapeutic inhibitors. For this purpose, along with checkpoint expression estimated by flow cytometry, we evaluated the time to progression (TTP) of MM patients at different clinical stages (disease diagnosis and relapse) depending on the checkpoint expression level; the cut-off point (dividing patients into low and high expressors) was selected based on the median value. Herein, we confirmed the defective levels of regulatory PD-1, CTLA-4 receptors, and the CD69 marker activation in newly diagnosed (ND) patients, whereas relapsed/refractory patients (RR) exhibited their recovered values and reactivity. Additionally, substantially higher populations of senescent CD4 + CD28 − T cells were found in MM, primarily in NDMM subjects. These observations suggest the existence of two dysfunctional states in MM CD4 T cells with the predominance of immunosenescence at disease diagnosis and exhaustion at relapse, thus implying different responsiveness to the external receptor blockade depending on the disease stage. Furthermore, we found that lower CTLA-4 levels in NDMM patients or higher PD-1 expression in RRMM patients may predict early relapse. In conclusion, ...
    Keywords multiple myeloma ; PD-1 ; CTLA-4 ; immune checkpoint inhibitors ; time to progression ; clinical response ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Deregulated Expression of Immune Checkpoints on Circulating CD4 T Cells May Complicate Clinical Outcome and Response to Treatment with Checkpoint Inhibitors in Multiple Myeloma Patients

    Anna Kulikowska de Nałęcz / Lidia Ciszak / Lidia Usnarska-Zubkiewicz / Irena Frydecka / Edyta Pawlak / Magdalena Szmyrka / Agata Kosmaczewska

    International Journal of Molecular Sciences, Vol 22, Iss 9298, p

    2021  Volume 9298

    Abstract: Unlike solid-tumor patients, a disappointingly small subset of multiple myeloma (MM) patients treated with checkpoint inhibitors derive clinical benefits, suggesting differential participation of inhibitory receptors involved in the development of T-cell- ...

    Abstract Unlike solid-tumor patients, a disappointingly small subset of multiple myeloma (MM) patients treated with checkpoint inhibitors derive clinical benefits, suggesting differential participation of inhibitory receptors involved in the development of T-cell-mediated immunosuppression. In fact, T cells in MM patients have recently been shown to display features of immunosenescence and exhaustion involved in immune response inhibition. Therefore, we aimed to identify the dominant inhibitory pathway in MM patients to achieve its effective control by therapeutic interventions. By flow cytometry, we examined peripheral blood (PB) CD4 T cell characteristics assigned to senescence or exhaustion, considering PD-1, CTLA-4, and BTLA checkpoint expression, as well as secretory effector function, i.e., capacity for IFN-γ and IL-17 secretion. Analyses were performed in a total of 40 active myeloma patients (newly diagnosed and treated) and 20 healthy controls. At the single-cell level, we found a loss of studied checkpoints’ expression on MM CD4 T cells (both effector (Teff) and regulatory (Treg) cells) primarily at diagnosis; the checkpoint deficit in MM relapse was not significant. Nonetheless, PD-1 was the only checkpoint distributed on an increased proportion of T cells in all MM patients irrespective of disease phase, and its expression on CD4 Teff cells correlated with adverse clinical courses. Among patients, the relative defect in secretory effector function of CD4 T cells was more pronounced at myeloma relapse (as seen in declined Th1/Treg and Th17/Treg cell rates). Although the contribution of PD-1 to MM clinical outcomes is suggestive, our study clearly indicated that the inappropriate expression of immune checkpoints (associated with dysfunctionality of CD4 T cells and disease clinical phase) might be responsible for the sub-optimal clinical response to therapeutic checkpoint inhibitors in MM.
    Keywords multiple myeloma ; CD4 T cells ; PD-1 ; CTLA-4 ; checkpoint inhibitors ; clinical outcome ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Differential Function of a Novel Population of the CD19+CD24hiCD38hi Bregs in Psoriasis and Multiple Myeloma

    Joanna Bartosińska / Joanna Purkot / Agnieszka Karczmarczyk / Michał Chojnacki / Joanna Zaleska / Paulina Własiuk / Norbert Grząśko / Marta Morawska / Adam Walter-Croneck / Lidia Usnarska-Zubkiewicz / Patrycja Zielińska / Krzysztof Jamroziak / Małgorzata Kowal / Dorota Krasowska / Grażyna Chodorowska / Krzysztof Giannopoulos

    Cells, Vol 10, Iss 411, p

    2021  Volume 411

    Abstract: Psoriasis (Ps), an autoimmune disease, and multiple myeloma (MM), a blood neoplasm, are characterized by immune dysregulation resulting from the imbalance between the effector and regulatory cells, including B regulatory (Breg) lymphocytes. Peripheral ... ...

    Abstract Psoriasis (Ps), an autoimmune disease, and multiple myeloma (MM), a blood neoplasm, are characterized by immune dysregulation resulting from the imbalance between the effector and regulatory cells, including B regulatory (Breg) lymphocytes. Peripheral blood samples from 80 Ps patients, 17 relapsed/refractory MM patients before and after daratumumab (anti-CD38 monoclonal antibody) treatment, 23 healthy volunteers (HVs), and bone marrow samples from 59 MM patients were used in the study. Bregs were determined by flow cytometry using CD19, CD24, and CD38. Intracellular production of interleukin-10 (IL-10) was assessed by flow cytometry after CD40L, LPS, and CpG stimulation. IL-10 serum or plasma concentrations were tested using ELISA method. The percentage of CD19+CD24hiCD38hi Bregs was not different whereas the production of IL-10 in Bregs was significantly higher in Ps patients in comparison with HVs. The percentage of CD19+CD24hiCD38hi Bregs in MM patients was significantly higher than in HVs ( p < 0.0001). The percentage of CD19+CD24hiCD38hi Bregs was significantly higher in MM patients with the ISS stage I ( p = 0.0233) while IL-10 production in Bregs was significantly higher in ISS stage III (p = 0.0165). IL-10 serum or plasma concentration was significantly higher in Ps and MM patients when compared to HVs ( p < 0.0001). Following the treatment with daratumumab the percentages of CD19+CD24hiCD38hi Bregs significantly decreased ( p < 0.0003). Here, in the two opposite immune conditions, despite the differences in percentages of Bregs in Ps and MM we have identified some similarities in the IL-10 producing Bregs. Effective treatment of daratumumab besides the anti-myeloma effect was accompanied by the eradication of Bregs.
    Keywords psoriasis ; multiple myeloma ; Bregs ; interleukin 10 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Bendamustine-Based Regimens as Salvage Therapy in Refractory/Relapsed Multiple Myeloma Patients

    Norbert Grzasko / Grzegorz Charlinski / Marta Morawska / Pawel Kicinski / Anna Waszczuk-Gajda / Joanna Drozd-Sokolowska / Edyta Subocz / Danuta Blonska / Malgorzata Razny / Agnieszka Druzd-Sitek / Jadwiga Holojda / Alina Swiderska / Lidia Usnarska-Zubkiewicz / Anna Masternak / Krzysztof Giannopoulos

    Journal of Clinical Medicine, Vol 10, Iss 5504, p

    A Retrospective Real-Life Analysis by the Polish Myeloma Group

    2021  Volume 5504

    Abstract: Multiple myeloma (MM) is an incurable disease and patients become refractory to the treatment in the course of the disease. Bendamustine-based regimens containing steroids and other agents are among the therapeutic options offered to MM patients. Here, ... ...

    Abstract Multiple myeloma (MM) is an incurable disease and patients become refractory to the treatment in the course of the disease. Bendamustine-based regimens containing steroids and other agents are among the therapeutic options offered to MM patients. Here, we investigated the safety and the efficacy of bendamustine used in patients with refractory/relapsed MM (RRMM). The patients were treated with bendamustine and steroids ( n = 52) or bendamustine, steroids and immunomodulatory agents or proteasome inhibitors ( n = 53). Response rates, progression-free survival (PFS), overall survival (OS) and frequency of adverse events were compared between both study groups. Most efficacy measurements were better in patients treated with three-drug regimens: overall response rate (55% versus 37%, p = 0.062), median PFS (9 months versus 4 months, p < 0.001), median OS survival (18 months versus 12 months, p = 0.679). The benefit from combining bendamustine and steroids with an additional agent was found in subgroups previously treated with both lenalidmide and bortezomib, with stem cell transplant and with more than two previous therapy lines. Toxicity was similar in both study groups and bendamustine-based therapies were generally well-tolerated. Our study suggests that bendamustine may be an effective treatment for patients with RRMM. Three-drug regimens containing bendamustine, steroids and novel agents produced better outcomes and had acceptable toxicity. The efficacy of bendamustine combined with steroids was limited.
    Keywords multiple myeloma ; bendamustine ; refractory/relapsed ; salvage therapy ; lenalidomide ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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