Browsing by Subject "MOLECULAR RESPONSE"

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  • Hjorth-Hansen, Henrik; Stenke, Leif; Soderlund, Stina; Dreimane, Arta; Ehrencrona, Hans; Gedde-Dahl, Tobias; Gjertsen, Bjorn Tore; Hoglund, Martin; Koskenvesa, Perttu; Lotfi, Kourosh; Majeed, Waleed; Markevarn, Berit; Ohm, Lotta; Olsson-Stromberg, Ulla; Remes, Kari; Suominen, Merja; Simonsson, Bengt; Porkka, Kimmo; Mustjoki, Satu; Richter, Johan; NCMLSG (2015)
  • Ilander, Mette; Kreutzman, Anna; Rohon, Peter; Melo, Teresa; Faber, Edgar; Porkka, Kimmo; Vakkila, Jukka; Mustjoki, Satu (2014)
  • Huuhtanen, Jani; Ilander, Mette; Yadav, Bhagwan; Dufva, Olli M. J.; Lähteenmäki, Hanna; Kasanen, Tiina; Klievink, Jay; Olsson-Strömberg, Ulla; Stentoft, Jesper; Richter, Johan; Koskenvesa, Perttu; Hoglund, Martin; Söderlund, Stina; Dreimane, Arta; Porkka, Kimmo; Gedde-Dahl, Tobias; Gjertsen, Bjorn T.; Stenke, Leif; Myhr-Eriksson, Kristina; Markevarn, Berit; Lubking, Anna; Dimitrijevic, Andreja; Udby, Lene; Bjerrum, Ole Weis; Hjorth-Hansen, Henrik; Mustjoki, Satu (2022)
    In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-alpha is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-alpha in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCR beta sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8(+) recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-alpha reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-alpha had costimulatory effects on TCR signaling. Our work supports the combination of IFN-alpha with TKI therapy, as IFN-alpha broadens the immune repertoire and restores immunological function.
  • Bruck, Oscar; Blom, Sami; Dufva, Olli; Turkki, Riku; Chheda, Himanshu; Ribeiro, Antonio; Kovanen, Panu; Aittokallio, Tero; Koskenvesa, Perttu; Kallioniemi, Olli; Porkka, Kimmo; Pellinen, Teijo; Mustjoki, Satu (2018)
    Increasing evidence suggests that the immune system affects prognosis of chronic myeloid leukemia (CML), but the detailed immunological composition of the leukemia bone marrow (BM) microenvironment is unknown. We aimed to characterize the immune landscape of the CML BM and predict the current treatment goal of tyrosine kinase inhibitor (TKI) therapy, molecular remission 4.0 (MR4.0). Using multiplex immunohistochemistry (mIHC) and automated image analysis, we studied BM tissues of CML patients (n = 56) and controls (n = 14) with a total of 30 immunophenotype markers essential in cancer immunology. CML patients' CD4+ and CD8+ T-cells expressed higher levels of putative exhaustion markers PD1, TIM3, and CTLA4 when compared to control. PD1 expression was higher in BM compared to paired peripheral blood (PB) samples, and decreased during TKI therapy. By combining clinical parameters and immune profiles, low CD4+ T-cell proportion, high proportion of PD1+ TIM3-CD8+ T cells, and high PB neutrophil count were most predictive of lower MR4.0 likelihood. Low CD4+ T-cell proportion and high PB neutrophil counts predicted MR4.0 also in a validation cohort (n = 52) analyzed with flow cytometry. In summary, the CML BM is characterized by immune suppression and immune biomarkers predicted MR4.0, thus warranting further testing of immunomodulatory drugs in CML treatment.
  • Flygt, Hjalmar; Söderlund, Stina; Stentoft, Jesper; Richter, Johan; Koskenvesa, Perttu; Mustjoki, Satu; Majeed, Waleed; Lubking, Anna; Dreimane, Arta; Markevarn, Berit; Stenke, Leif; Myhr Eriksson, Kristina; Gjertsen, Bjorn Tore; Gedde-Dahl, Tobias; Dimitrijevic, Andreja; Udby, Lene; Olsson-Stromberg, Ulla; Hjorth-Hansen, Henrik (2021)
    Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-alpha in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-alpha (PegIFN-alpha) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 mu g/wk of PegIFN-alpha was added and increased to 25 mu g/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-alpha to DAS shows good long-term efficacy without increased toxicity.
  • Gullaksen, Stein-Erik; Skavland, Jorn; Gavasso, Sonia; Tosevski, Vinko; Warzocha, Krzysztof; Dumrese, Claudia; Ferrant, Augustin; Gedde-Dahl, Tobias; Hellmann, Andrzej; Janssen, Jeroen; Labar, Boris; Lang, Alois; Majeed, Waleed; Mihaylov, Georgi; Stentoft, Jesper; Stenke, Leif; Thaler, Josef; Thielen, Noortje; Verhoef, Gregor; Voglova, Jaroslava; Ossenkoppele, Gert; Hochhaus, Andreas; Hjorth-Hansen, Henrik; Mustjoki, Satu; Sopper, Sieghart; Giles, Francis; Porkka, Kimmo; Wolf, Dominik; Gjertsen, Bjorn Tore (2017)
    Monitoring of single cell signal transduction in leukemic cellular subsets has been proposed to provide deeper understanding of disease biology and prognosis, but has so far not been tested in a clinical trial of targeted therapy. We developed a complete mass cytometry analysis pipeline for characterization of intracellular signal transduction patterns in the major leukocyte subsets of chronic phase chronic myeloid leukemia. Changes in phosphorylated Bcr-Abl1 and the signaling pathways involved were readily identifiable in peripheral blood single cells already within three hours of the patient receiving oral nilotinib. The signal transduction profiles of healthy donors were clearly distinct from those of the patients at diagnosis. Furthermore, using principal component analysis, we could show that phosphorylated transcription factors STAT3 (Y705) and CREB (S133) within seven days reflected BCR-ABL1(IS) at three and six months. Analyses of peripheral blood cells longitudinally collected from patients in the ENEST1st clinical trial showed that single cell mass cytometry appears to be highly suitable for future investigations addressing tyrosine kinase inhibitor dosing and effect. (clinicaltrials. gov identifier: 01061177)