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JOURNAL ARTICLE
Vania Lo Presti, Angelo Meringa, Ester Dunnebach, Alice van Velzen, Aida Valera Moreira, Ronald W Stam, Rishi S Kotecha, Anja Krippner-Heidenreich, Olaf T Heidenreich, Maud Plantinga, Annelisa Cornel, Zsolt Sebestyen, Jurgen Kuball, Niek P van Til, S Nierkens
BACKGROUND: Hematopoietic cell transplantation (HCT) is an effective treatment for pediatric patients with high-risk, refractory, or relapsed acute myeloid leukemia (AML). However, a large proportion of transplanted patients eventually die due to relapse. To improve overall survival, we propose a combined strategy based on cord blood (CB)-HCT with the application of AML-specific T cell receptor (TCR)-engineered T cell therapy derived from the same CB graft. METHODS: We produced CB-CD8+ T cells expressing a recombinant TCR (rTCR) against Wilms tumor 1 (WT1) while lacking endogenous TCR (eTCR) expression to avoid mispairing and competition...
April 5, 2024: Journal for Immunotherapy of Cancer
#2
JOURNAL ARTICLE
Shanice Beerepoot, Jaap Jan Boelens, Caroline Lindemans, Moniek A de Witte, Stefan Nierkens, Alexander F J E Vrancken, Marjo S van der Knaap, Marianna Bugiani, Nicole I Wolf
Metachromatic leukodystrophy (MLD) is a neuro-metabolic disorder due to arylsulfatase A deficiency, causing demyelination of the central and peripheral nervous system. Hematopoietic cell transplantation (HCT) can provide a symptomatic and survival benefit for pre-symptomatic and early symptomatic patients by stabilizing CNS disease. This case series, however, illustrates the occurrence of severely progressive polyneuropathy shortly after HCT in two patients with late-infantile, one with late-juvenile, and one with adult MLD, leading to the inability to walk or sit without support...
April 2, 2024: Journal of Neurology
#3
REVIEW
Caitlyn Forbes, Stefan Nierkens, Annelisa M Cornel
Natural killer (NK)-cells are innate immune cells with potent anti-tumor capacity, capable of recognizing target cells without prior exposure. For this reason, NK-cells are recognized as a useful source of cell therapy. Although most NK-cells are derived from the bone marrow (BM), a separate developmental pathway in the thymus also exists, producing so-called thymic NK-cells. Unlike conventional NK-cells, thymic NK (tNK)-cells have a combined capacity for cytokine production and a natural ability to kill tumor cells in the presence of NK-cell receptor stimulatory ligands...
2024: ImmunoTargets and Therapy
#4
JOURNAL ARTICLE
Annelisa M Cornel, Loutje van der Sman, Jip T van Dinter, Marta Arrabito, Ester Dunnebach, Marliek van Hoesel, Thomas A Kluiver, Ana P Lopes, Noël M M Dautzenberg, Linde Dekker, Jorik M van Rijn, Denise A M H van den Beemt, Juliane L Buhl, Aimee du Chatinier, Farnaz Barneh, Yuyan Lu, Luca Lo Nigro, Anja Krippner-Heidenreich, Zsolt Sebestyén, Jurgen Kuball, Esther Hulleman, Jarno Drost, Sebastiaan van Heesch, Olaf T Heidenreich, Weng Chuan Peng, Stefan Nierkens
Human leukocyte antigen (HLA) restriction of conventional T-cell targeting introduces complexity in generating T-cell therapy strategies for patients with cancer with diverse HLA-backgrounds. A subpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant T-cells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancer-specific metabolites. It is hypothesized that the MC.7.G5 MR1T-clone has potential as a pan-cancer, pan-population T-cell immunotherapy approach...
March 21, 2024: Journal for Immunotherapy of Cancer
#5
REVIEW
Maria Alieva, Mario Barrera Román, Sam de Blank, Diana Petcu, Amber L Zeeman, Noël M M Dautzenberg, Annelisa M Cornel, Cesca van de Ven, Rob Pieters, Monique L den Boer, Stefan Nierkens, Friso G J Calkoen, Hans Clevers, Jürgen Kuball, Zsolt Sebestyén, Ellen J Wehrens, Johanna F Dekkers, Anne C Rios
Modeling immuno-oncology by using patient-derived material and immune cell co-cultures can advance our understanding of immune cell tumor targeting in a patient-specific manner, offering leads to improve cellular immunotherapy. However, fully exploiting these living cultures requires analysis of the dynamic cellular features modeled, for which protocols are currently limited. Here, we describe the application of BEHAV3D, a platform that implements multi-color live 3D imaging and computational tools for: (i) analyzing tumor death dynamics at both single-organoid or cell and population levels, (ii) classifying T cell behavior and (iii) producing data-informed 3D images and videos for visual inspection and further insight into obtained results...
March 19, 2024: Nature Protocols
#6
JOURNAL ARTICLE
Rick Admiraal, A Birgitta Versluijs, Alwin D R Huitema, Lysette Ebskamp, Amelia Lacna, C T Klaartje de Kanter, Marc B Bierings, Jaap Jan Boelens, Caroline A Lindemans, Stefan Nierkens
BACKGROUND: Graft-versus-host disease (GvHD) and rejection are main limitations of cord blood transplantation (CBT), more so in patients with severe inflammation or previous rejections. While rigorous T-cell depletion with antithymocyte globulin (ATG) is needed to prevent GvHD and rejection, overexposure to ATG leads to slow T-cell recovery after transplantation, especially in CBT. OBJECTIVE: To evaluate high-dose, upfront ATG with individualized dosing and therapeutic drug monitoring (TDM) in pediatric CBT for patients at high risk for GvHD and rejection...
February 23, 2024: Cytotherapy
#7
JOURNAL ARTICLE
Mandy W E Smeets, Elisabeth M P Steeghs, Jan Orsel, Femke Stalpers, Myrthe M P Vermeeren, Christina H J Veltman, Lotte Slenders, Stefan Nierkens, Cesca Van de Ven, Monique L Den Boer
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can hijack the normal bone marrow microenvironment to create a leukemic niche which facilitates blast cell survival and promotes drug resistance. Bone marrow-derived mesenchymal stromal cells (MSCs) mimic this protective environment in ex vivo co-cultures with leukemic cells obtained from children with newly diagnosed BCP-ALL. We examined the potential mechanisms of this protection by RNA sequencing of flowsorted MSCs after co-culture with BCP-ALL cells...
February 29, 2024: Haematologica
#8
JOURNAL ARTICLE
Claus-Philipp Maier, Chihab Klose, Christian Martin Seitz, Florian Heubach, Michaela Döring, Roland Meisel, Friedhelm R Schuster, Bernd Gruhn, Frieder Keller, Armin Rabsteyn, Anne-Marie Arendt, Germano Amorelli, Thomas Eichholz, Tobias Feuchtinger, Holger Martinius, Stefan Nierkens, Rouwen Teltschik, Johannes Hubertus Schulte, Claudia Lengerke, Rupert Handgretinger, Peter Lang
Anti-T lymphocyte globulin (ATLG) significantly reduces the risk of engraftment failure in allogeneic hematopoietic stem cell transplantation (HSCT), but hampers post-transplant immune reconstitution. We hypothesized that in patients receiving haploidentical CD3/CD19-depleted grafts these double-edged effects could be better balanced by attaining high ATLG serum concentrations before transplant, but as low as possible on the day of transplant. Therefore, we moved the start of ATLG application to day -12 and determined serum concentrations of T cell specific ATLG in pediatric patients treated with three established dosing regimens (15, 30, or 60 mg/kg)...
January 30, 2024: Blood Advances
#9
JOURNAL ARTICLE
Natalie I Mazur, Yvette N Löwensteyn, Jonne Terstappen, Jeanette Leusen, Fred Schobben, Daniela Cianci, Peter M van de Ven, Stefan Nierkens, Louis J Bont
BACKGROUND: Mucosal administration of monoclonal antibodies (mAbs) against respiratory pathogens is a promising alternative for systemic administration because lower doses are required for protection. Clinical development of mucosal mAbs is a highly active field yet clinical proof-of-concept is lacking. METHODS: In this investigator-initiated, double-blind, randomized placebo-controlled trial, we evaluated intranasal palivizumab for the prevention of RSV infection in preterm infants (Dutch Trial Register NTR7378 and NTR7403)...
December 2023: EClinicalMedicine
#10
JOURNAL ARTICLE
Judith Wienke, Lindy L Visser, Waleed M Kholosy, Kaylee M Keller, Marta Barisa, Evon Poon, Sophie Munnings-Tomes, Courtney Himsworth, Elizabeth Calton, Ana Rodriguez, Ronald Bernardi, Femke van den Ham, Sander R van Hooff, Yvette A H Matser, Michelle L Tas, Karin P S Langenberg, Philip Lijnzaad, Anne L Borst, Elisa Zappa, Francisca J Bergsma, Josephine G M Strijker, Bronte M Verhoeven, Shenglin Mei, Amira Kramdi, Restuadi Restuadi, Alvaro Sanchez-Bernabeu, Annelisa M Cornel, Frank C P Holstege, Juliet C Gray, Godelieve A M Tytgat, Marijn A Scheijde-Vermeulen, Marc H W A Wijnen, Miranda P Dierselhuis, Karin Straathof, Sam Behjati, Wei Wu, Albert J R Heck, Jan Koster, Stefan Nierkens, Isabelle Janoueix-Lerosey, Ronald R de Krijger, Ninib Baryawno, Louis Chesler, John Anderson, Hubert N Caron, Thanasis Margaritis, Max M van Noesel, Jan J Molenaar
Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. Since novel and improved immunotherapies may fill this need, we dissect the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 24 tumors (10 pre- and 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated by natural killer (NK), T and B cells, and immunosuppressive myeloid populations...
February 12, 2024: Cancer Cell
#11
Joost B Koedijk, Inge van der Werf, Livius Penter, Marijn A Vermeulen, Farnaz Barneh, Alicia Perzolli, Joyce I Meesters-Ensing, Marta Fiocco, Hester A de Groot-Kruseman, Rubina Moeniralam, Kristina Bang Christensen, Billie Porter, Kathleen Pfaff, Jacqueline S Garcia, Scott J Rodig, Catherine J Wu, Henrik Hasle, Stefan Nierkens, Mirjam E Belderbos, C Michel Zwaan, Olaf Heidenreich
UNLABELLED: Because of the low mutational burden, children with acute myeloid leukemia (AML) are thought to have a 'cold' tumor microenvironment and consequently, a low likelihood of response to T cell-directed immunotherapies. Here, we provide a multidimensional overview of the tumor immune microenvironment in newly diagnosed pediatric AML. On a cohort level, we demonstrate wide variation in T cell infiltration with nearly one-third of cases harboring an immune-infiltrated bone marrow...
October 30, 2023: medRxiv
#12
Joost B Koedijk, Thomas B van Beek, Marijn A Vermeulen, Lennart A Kester, Elizabeth K Schweighart, Stefan Nierkens, Mirjam E Belderbos, C Michel Zwaan, Katja M J Heitink-Pollé, Olaf Heidenreich
Regression of leukemia in the absence of disease-modifying therapy remains poorly understood, although immunological mechanisms are thought to play a role. Here, we present a unique case of a 17-year-old boy with immune dysregulation and long-lasting regression of a (pre)leukemic clone in the absence of disease-modifying therapy. Using molecular and immunological analyses, we identified bone marrow features associated with disease control and loss thereof. In addition, our case reveals that detection of certain fusion genes with hardly any blasts in the bone marrow may be indicative of an accompanying oncogenic fusion gene, with implications for disease surveillance- and management in future patients...
2023: Frontiers in Immunology
#13
JOURNAL ARTICLE
Mick J M van Eijs, Rik J Verheijden, Stefanie A van der Wees, Stefan Nierkens, Anne S R van Lindert, Karijn P M Suijkerbuijk, Femke van Wijk
Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of advanced malignancies, but come with a diverse spectrum of immune-related adverse events (irAEs). Mechanistic studies can aid the transition from expert-opinion to evidence-based irAE treatment strategies. We aimed to longitudinally characterize peripheral blood T and B cell dynamics in ICI-treated patients by multicolor flow cytometry and serum multiplex immunoassay at baseline, ± 3 weeks and ± 6 weeks or upon clinically relevant irAEs...
October 4, 2023: Cancer Immunology, Immunotherapy: CII
#14
JOURNAL ARTICLE
Mick J M van Eijs, José J M Ter Linde, Matthijs J D Baars, Mojtaba Amini, Miangela M Laclé, Eelco C Brand, Eveline M Delemarre, Julia Drylewicz, Stefan Nierkens, Rik J Verheijden, Bas Oldenburg, Yvonne Vercoulen, Karijn P M Suijkerbuijk, Femke van Wijk
Colitis is a prevalent adverse event associated with immune checkpoint inhibitor (ICI) therapy with similarities to inflammatory bowel disease. Incomplete mechanistic understanding of ICI colitis curtails evidence-based treatment. Given the often-overlooked connection between tissue architecture and mucosal immune cell function, we here applied imaging mass cytometry (IMC) to gain spatial proteomic insight in ICI colitis in comparison to ulcerative colitis (UC). Using a cell segmentation pipeline that simultaneously utilizes high-resolution nuclear imaging and high-multiplexity IMC, we show that intra-epithelial CD8+ T cells are significantly more abundant (and numerically dominant) in anti-PD-1 ± anti-CTLA-4-induced colitis compared to anti-CTLA-4-induced colitis and UC...
October 20, 2023: IScience
#15
JOURNAL ARTICLE
Yu-Hsiang Chiu, Anouk Drijver, Rick Admiraal, Anna van Rhenen, Stefan Nierkens, Jacob M van Laar, Julia Spierings
INTRODUCTION: Autologous haematopoietic stem cell transplantation improves event-free survival and lung function and reduces skin thickening in patients with progressive diffuse cutaneous systemic sclerosis. Anti-thymocyte globulin is a key lymphoablative constituent of conditioning protocols and is administered in a weight-based dosage. However, whether anti-thymocyte globulin exposure contributes to response to autologous haematopoietic stem cell transplantation and lymphocyte reconstitution in diffuse cutaneous systemic sclerosis patients is unknown...
October 2023: Journal of Scleroderma and related Disorders
#16
JOURNAL ARTICLE
Martijn W C Verbeek, Beatriz Soriano Rodríguez, Lukasz Sedek, Anna Laqua, Chiara Buracchi, Malicorne Buysse, Michaela Reiterová, Elen Oliveira, Daniela Morf, Sjoerd R Oude Alink, Susana Barrena, Saskia Kohlscheen, Stefan Nierkens, Mattias Hofmans, Paula Fernandez, Elaine Sobral de Costa, Ester Mejstrikova, Tomasz Szczepanski, Lukasz Slota, Monika Brüggemann, Giuseppe Gaipa, Georgiana Grigore, Jacques J M van Dongen, Alberto Orfao, Vincent H J van der Velden
Presence of minimal residual disease (MRD), detected by flow cytometry, is an important prognostic biomarker in the management of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, data-analysis remains mainly expert-dependent. In this study, we designed and validated an Automated Gating & Identification (AGI) tool for MRD analysis in BCP-ALL patients using the two tubes of the EuroFlow 8-color MRD panel. The accuracy, repeatability, and reproducibility of the AGI tool was validated in a multicenter study using bone marrow follow-up samples from 174 BCP-ALL patients, stained with the EuroFlow BCP-ALL MRD panel...
September 22, 2023: Cytometry. Part B, Clinical Cytometry
#17
JOURNAL ARTICLE
Pauline Schneider, Nicholas T Crump, Susan T C J M Arentsen-Peters, Alastair L Smith, Rico Hagelaar, Fabienne R S Adriaanse, Romy S Bos, Anja de Jong, Stefan Nierkens, Bianca Koopmans, Thomas A Milne, Rob Pieters, Ronald W Stam
In KMT2A-rearranged acute lymphoblastic leukemia (ALL), an aggressive malignancy, oncogenic KMT2A-fusion proteins inappropriately recruit DOT1L to promote leukemogenesis, highlighting DOT1L as an attractive therapeutic target. Unfortunately, treatment with the first-in-class DOT1L inhibitor pinometostat eventually leads to non-responsiveness. To understand this we established acquired pinometostat resistance in pediatric KMT2A::AFF1+ B-ALL cells. Interestingly, these cells became mostly independent of DOT1L-mediated H3K79 methylation, but still relied on the physical presence of DOT1L, HOXA9 and the KMT2A::AFF1 fusion...
September 22, 2023: Experimental Hematology & Oncology
#18
JOURNAL ARTICLE
Cristina Bugarin, Laura Antolini, Chiara Buracchi, Sergio Matarraz, Tiziana Angela Coliva, Vincent H Van der Velden, Tomasz Szczepanski, Elaine Sobral Da Costa, Alita Van der Sluijs, Michaela Novakova, Ester Mejstrikova, Stefan Nierkens, Fabiana Vieira De Mello, Paula Fernandez, Carmen Aanei, Łukasz Sędek, Luisa Strocchio, Riccardo Masetti, Laura Sainati, Jan Philippé, Maria Grazia Valsecchi, Franco Locatelli, Jacques J M Van Dongen, Andrea Biondi, Alberto Orfao, Giuseppe Gaipa
Diagnostic criteria for juvenile myelomonocytic leukemia (JMML) are currently well defined, however in some patients diagnosis still remains a challenge. Flow cytometry is a well-established tool for diagnosis and follow-up of hematological malignancies, nevertheless it is not routinely used for JMML diagnosis. Herewith, we characterized the CD34+ hematopoietic precursor cells collected from 31 children with JMML using a combination of standardized EuroFlow antibody panels to assess the ability to discriminate JMML cells from normal/reactive bone marrow cell as controls (n=29) or from cells of children with other hematological diseases mimicking JMML (n=9)...
August 3, 2023: Haematologica
#19
JOURNAL ARTICLE
Paula Niewold, Douwe J Dijkstra, Yi Cai, Delia Goletti, Fabrizio Palmieri, Krista E van Meijgaarden, Frank A W Verreck, Onno W Akkerman, Regina W Hofland, Eveline M Delemarre, Stefan Nierkens, Marije K Verheul, Andrew J Pollard, Jaap T van Dissel, Tom H M Ottenhoff, Leendert A Trouw, Simone A Joosten
Tuberculosis (TB) is a prevalent disease causing an estimated 1.6 million deaths and 10.6 million new cases annually. Discriminating TB disease from differential diagnoses can be complex, particularly in the field. Increased levels of complement component C1q in serum have been identified as a specific and accessible biomarker for TB disease but the source of C1q in circulation has not been identified. Here, data and samples previously collected from human cohorts, a clinical trial and a non-human primate study were used to identify cells producing C1q in circulation...
July 18, 2023: Scientific Reports
#20
JOURNAL ARTICLE
Alexandre G Troullioud Lucas, Caroline A Lindemans, Senthil Velan Bhoopalan, Rana Dandis, Susan E Prockop, Swati Naik, Dinesh Keerthi, Coco de Koning, Akshay Sharma, Stefan Nierkens, Jaap Jan Boelens
BACKGROUND AIMS: CD4 immune reconstitution (IR) after allogeneic hematopoietic cell transplant (allo-HCT) correlates with lower non-relapse mortality (NRM), but its impact on leukemia relapse remains less clear, especially in children. We studied the correlation between IR of lymphocyte subsets and HCT outcomes in a large cohort of children/young adults with hematological malignancies. METHODS: We retrospectively analyzed CD4, CD8, B-cell and natural killer (NK) cell reconstitution in patients after first allo-HCT for a hematological malignancy at three large academic institutions (n = 503; period 2008-2019)...
June 16, 2023: Cytotherapy
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