30 results on '"Schaap, Nicolaas P. M."'
Search Results
2. Endothelial Activation and Stress Index (EASIX) to predict mortality after allogeneic stem cell transplantation: a prospective study
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Penack, Olaf, primary, Luft, Thomas, additional, Peczynski, Christophe, additional, Benner, Axel, additional, Sica, Simona, additional, Arat, Mutlu, additional, Itäla-Remes, Maija, additional, Corral, Lucia López, additional, Schaap, Nicolaas P M, additional, Karas, Michal, additional, Raida, Ludek, additional, Schroeder, Thomas, additional, Dreger, Peter, additional, Metafuni, Elisabetta, additional, Ozcelik, Tulay, additional, Sandmaier, Brenda M, additional, Kordelas, Lambros, additional, Moiseev, Ivan, additional, Schoemans, Hélène, additional, Koenecke, Christian, additional, Basak, Grzegorz W, additional, and Peric, Zinaida, additional
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- 2024
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3. Cell composition and expansion strategy can reduce the beneficial effect of AKT-inhibition on functionality of CD8+ T cells
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Mousset, Charlotte M., Hobo, Willemijn, de Ligt, Aafke, Baardman, Sjoerd, Schaap, Nicolaas P. M., Jansen, Joop H., van der Waart, Anniek B., and Dolstra, Harry
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- 2020
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4. Human CD34+-derived complete plasmacytoid and conventional dendritic cell vaccine effectively induces antigen-specific CD8+ T cell and NK cell responses in vitro and in vivo.
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van Eck van der Sluijs, Jesper, van Ens, Diede, Brummelman, Jolanda, Heister, Daan, Sareen, Aastha, Truijen, Lisa, van Ingen Schenau, Dorette S., Heemskerk, Mirjam H. M., Griffioen, Marieke, Kester, Michel G. D., Schaap, Nicolaas P. M., Jansen, Joop H., van der Waart, Anniek B., Dolstra, Harry, and Hobo, Willemijn
- Abstract
Allogeneic stem cell transplantation (alloSCT) can be curative for hemato-oncology patients due to effective graft-versus-tumor immunity. However, relapse remains the major cause of treatment failure, emphasizing the need for adjuvant immunotherapies. In this regard, post-transplantation dendritic cell (DC) vaccination is a highly interesting strategy to boost graft-versus-tumor responses. Previously, we developed a clinically applicable protocol for simultaneous large-scale generation of end-stage blood DC subsets from donor-derived CD34
+ stem cells, including conventional type 1 and 2 DCs (cDC1s and cDC2s), and plasmacytoid DCs (pDCs). In addition, the total cultured end-product (DC-complete vaccine), also contains non-end-stage-DCs (i.e. non-DCs). In this study, we aimed to dissect the phenotypic identity of these non-DCs and their potential immune modulatory functions on the potency of cDCs and pDCs in stimulating tumor-reactive CD8+ T and NK cell responses, in order to obtain rationale for clinical translation of our DC-complete vaccine. The non-DC compartment was heterogeneous and comprised of myeloid progenitors and (immature) granulocyte- and monocyte-like cells. Importantly, non-DCs potentiated toll-like receptor-induced DC maturation, as reflected by increased expression of co-stimulatory molecules and enhanced cDC-derived IL-12 and pDC-derived IFN-α production. Additionally, antigen-specific CD8+ T cells effectively expanded upon DC-complete vaccination in vitro and in vivo. This effect was strongly augmented by non-DCs in an antigen-independent manner. Moreover, non-DCs did not impair in vitro DC-mediated NK cell activation, degranulation nor cytotoxicity. Notably, in vivo i.p. DC-complete vaccination activated i.v. injected NK cells. Together, these data demonstrate that the non-DC compartment potentiates DC-mediated activation and expansion of antigen-specific CD8+ T cells and do not impair NK cell responses in vitro and in vivo. This underscores the rationale for further clinical translation of our CD34+ -derived DC-complete vaccine in hemato-oncology patients post alloSCT. [ABSTRACT FROM AUTHOR]- Published
- 2023
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5. Invasive Fungal Disease in Patients with Myeloid Malignancies: A Retrospective Cohort Study of a Diagnostic-Driven Care Pathway Withholding Mould-Active Prophylaxis
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De Kort, Elizabeth A., primary, Buil, Jochem B., additional, Schalekamp, Steven, additional, Schaefer-Prokop, Cornelia, additional, Verweij, Paul E., additional, Schaap, Nicolaas P. M., additional, Blijlevens, Nicole M. A., additional, and Van der Velden, Walter J. F. M., additional
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- 2022
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6. Clinically applicable CD34+-derived blood dendritic cell subsets exhibit key subset-specific features and potently boost anti-tumor T and NK cell responses
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van Eck van der Sluijs, Jesper, van Ens, Diede, Thordardottir, Soley, Vodegel, Denise, Hermens, Inge, van der Waart, Anniek B., Falkenburg, J. H. Frederik, Kester, Michel G. D., de Rink, Iris, Heemskerk, Mirjam H. M., Borst, Jannie, Schaap, Nicolaas P. M., Jansen, Joop H., Xiao, Yanling, Dolstra, Harry, and Hobo, Willemijn
- Subjects
CD34+ hematopoietic progenitor cells ,Cancer Research ,T-Lymphocytes ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,medicine.medical_treatment ,Immunology ,Cell ,Cell Culture Techniques ,T cells ,CD34 ,Antigens, CD34 ,CD34(+) hematopoietic progenitor cells ,NK cells ,Biology ,Lymphocyte Activation ,Dendritic cells ,03 medical and health sciences ,Cross-Priming ,0302 clinical medicine ,Immunity ,medicine ,Humans ,Immunology and Allergy ,030304 developmental biology ,Antigen Presentation ,0303 health sciences ,Vaccination ,Dendritic cell ,Immunotherapy ,Hematopoietic Stem Cells ,Acquired immune system ,Clinical application ,Killer Cells, Natural ,Transplantation ,medicine.anatomical_structure ,Oncology ,Cancer research ,Original Article ,Stem cell ,030215 immunology - Abstract
Allogeneic stem cell transplantation (alloSCT), following induction chemotherapy, can be curative for hemato-oncology patients due to powerful graft-versus-tumor immunity. However, disease recurrence remains the major cause of treatment failure, emphasizing the need for potent adjuvant immunotherapy. In this regard, dendritic cell (DC) vaccination is highly attractive, as DCs are the key orchestrators of innate and adaptive immunity. Natural DC subsets are postulated to be more powerful compared with monocyte-derived DCs, due to their unique functional properties and cross-talk capacity. Yet, obtaining sufficient numbers of natural DCs, particularly type 1 conventional DCs (cDC1s), is challenging due to low frequencies in human blood. We developed a clinically applicable culture protocol using donor-derived G-CSF mobilized CD34+ hematopoietic progenitor cells (HPCs) for simultaneous generation of high numbers of cDC1s, cDC2s and plasmacytoid DCs (pDCs). Transcriptomic analyses demonstrated that these ex vivo-generated DCs highly resemble their in vivo blood counterparts. In more detail, we demonstrated that the CD141+CLEG9A+ cDC1 subset exhibited key features of in vivo cDC1s, reflected by high expression of co-stimulatory molecules and release of IL-12p70 and TNF-α. Furthermore, cDC1s efficiently primed alloreactive T cells, potently cross-presented long-peptides and boosted expansion of minor histocompatibility antigen-experienced T cells. Moreover, they strongly enhanced NK cell activation, degranulation and anti-leukemic reactivity. Together, we developed a robust culture protocol to generate highly functional blood DC subsets for in vivo application as tailored adjuvant immunotherapy to boost innate and adaptive anti-tumor immunity in alloSCT patients.
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- 2021
7. Clinically applicable CD34+-derived blood dendritic cell subsets exhibit key subset-specific features and potently boost anti-tumor T and NK cell responses.
- Author
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van Eck van der Sluijs, Jesper, van Ens, Diede, Thordardottir, Soley, Vodegel, Denise, Hermens, Inge, van der Waart, Anniek B., Falkenburg, J. H. Frederik, Kester, Michel G. D., de Rink, Iris, Heemskerk, Mirjam H. M., Borst, Jannie, Schaap, Nicolaas P. M., Jansen, Joop H., Xiao, Yanling, Dolstra, Harry, and Hobo, Willemijn
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KILLER cells ,BLOOD cells ,DENDRITIC cells ,T cells ,PROGENITOR cells - Abstract
Allogeneic stem cell transplantation (alloSCT), following induction chemotherapy, can be curative for hemato-oncology patients due to powerful graft-versus-tumor immunity. However, disease recurrence remains the major cause of treatment failure, emphasizing the need for potent adjuvant immunotherapy. In this regard, dendritic cell (DC) vaccination is highly attractive, as DCs are the key orchestrators of innate and adaptive immunity. Natural DC subsets are postulated to be more powerful compared with monocyte-derived DCs, due to their unique functional properties and cross-talk capacity. Yet, obtaining sufficient numbers of natural DCs, particularly type 1 conventional DCs (cDC1s), is challenging due to low frequencies in human blood. We developed a clinically applicable culture protocol using donor-derived G-CSF mobilized CD34
+ hematopoietic progenitor cells (HPCs) for simultaneous generation of high numbers of cDC1s, cDC2s and plasmacytoid DCs (pDCs). Transcriptomic analyses demonstrated that these ex vivo-generated DCs highly resemble their in vivo blood counterparts. In more detail, we demonstrated that the CD141+ CLEG9A+ cDC1 subset exhibited key features of in vivo cDC1s, reflected by high expression of co-stimulatory molecules and release of IL-12p70 and TNF-α. Furthermore, cDC1s efficiently primed alloreactive T cells, potently cross-presented long-peptides and boosted expansion of minor histocompatibility antigen-experienced T cells. Moreover, they strongly enhanced NK cell activation, degranulation and anti-leukemic reactivity. Together, we developed a robust culture protocol to generate highly functional blood DC subsets for in vivo application as tailored adjuvant immunotherapy to boost innate and adaptive anti-tumor immunity in alloSCT patients. [ABSTRACT FROM AUTHOR]- Published
- 2021
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8. Phase I/II trial of a combination of anti-CD3/CD7 immunotoxins for steroid-refractory acute graft-versus-host disease
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Groth, Christoph, van Groningen, Lenneke F J, Matos, Tiago R, Bremmers, Manita E, Preijers, Frank W M B, Dolstra, Harry, Reicherts, Christian, Schaap, Nicolaas P M, van Hooren, Eric H G, IntHout, Joanna, Netea, Mihai G, Masereeuw, Rosalinde, Levine, John E, Morales, George, Ferrara, James L, Blijlevens, Nicole M A, van Oosterhout, Ypke V J M, Stelljes, Matthias, van der Velden, Walter J F M, Afd Pharmacology, Pharmacology, Dermatology, Graduate School, AII - Inflammatory diseases, Afd Pharmacology, and Pharmacology
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Adult ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,T cell ,CD3 ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Graft vs Host Disease ,Gastroenterology ,Article ,Young Adult ,Immune system ,All institutes and research themes of the Radboud University Medical Center ,Immunotoxin ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Hypoalbuminemia ,Prospective Studies ,Adverse effect ,Aged ,Transplantation ,Acute graft-versus-host disease ,biology ,business.industry ,Immunotoxins ,Immunosuppression ,Hematology ,Middle Aged ,medicine.disease ,Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] ,medicine.anatomical_structure ,Acute Disease ,biology.protein ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,Allogenic hematopoietic stem cell transplantation ,Antibody ,business ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Effective therapies for treating patients with steroid-refractory acute graft-versus-host-disease (SR-aGVHD), particularly strategies that reduce the duration of immunosuppression following remission, are urgently needed. The investigated immunotoxin combination consists of a mixture of anti-CD3 and anti-CD7 antibodies separately conjugated to recombinant ricin A (CD3/CD7-IT), which induces in vivo depletion of T cells and natural killer (NK) cells and suppresses T cell receptor activation. We conducted a phase I/II trial to examine the safety and efficacy of CD3/CD7-IT in 20 patients with SR-aGVHD; 17 of these patients (85%) had severe SR-aGVHD, and all 20 patients had visceral organ involvement, including 18 (90%) with gastrointestinal (GI) involvement and 5 (25%) with liver involvement. A validated 2-biomarker algorithm classified the majority of patients (11 of 20) as high risk. On day 28 after the start of CD3/CD7-IT therapy, the overall response rate was 60% (12 of 20), with 10 patients (50%) achieving a complete response. The 6-month overall survival rate was 60% (12 of 20), including 64% (7 of 11) classified as high risk by biomarkers. The 1-week course of treatment with CD3/CD7-IT caused profound but transient depletion of T cells and NK cells, followed by rapid recovery of the immune system with a diverse TCR Vβ repertoire, and preservation of Epstein-Barr virus- and cytomegalovirus-specific T cell clones. Furthermore, our results indicate that CD3/CD7-IT appeared to be safe and well tolerated, with a relatively low prevalence of manageable and reversible adverse events, primarily worsening of hypoalbuminemia, microangiopathy, and thrombocytopenia. These encouraging results suggest that CD3/CD7-IT may improve patient outcomes in patients with SR-aGVHD.
- Published
- 2019
9. CD34+ progenitor-derived NK cell and gemcitabine combination therapy increases killing of ovarian cancer cells in NOD/SCID/IL2Rgnull mice.
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Van der Meer, Jolien M. R., de Jonge, Paul K. J. D., van der Waart, Anniek B., Geerlings, Alexander C., Moonen, Jurgen P., Brummelman, Jolanda, de Klein, Janne, Vermeulen, Malou C., Maas, Ralph J. A., Schaap, Nicolaas P. M., Hoogstad-van Evert, Janneke S., Ottevanger, Petronella B., Jansen, Joop H., Hobo, Willemijn, and Dolstra, Harry
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OVARIAN cancer ,KILLER cells ,CANCER cells ,GEMCITABINE ,DEATH receptors ,CELLULAR immunity - Abstract
Combining natural killer (NK) cell adoptive transfer with tumor-sensitizing chemotherapy is an attractive approach against recurrent ovarian cancer (OC), as OC is sensitive to NK cell-mediated immunity. Previously, we showed that CD34
+ hematopoietic progenitor cell (HPC)-derived NK cells can kill OC cells in vitro and inhibit OC tumor growth in mice. Here, we investigated the potential of HPC-NK cell therapy combined with chemotherapeutic gemcitabine (used in recurrent OC patients) against OC. We examined the phenotypical, functional, and cytotoxic effects of gemcitabine on HPC-NK cells and/or OC cells in vitro and in OC-bearing mice. To this end, we treated OC cells and/or HPC-NK cells with or without gemcitabine and analyzed the phenotype, cytokine production, and anti-tumor reactivity. We found that gemcitabine did not affect the phenotype and functionality of HPC-NK cells, while on OC cells expression of NK cell activating ligands and death receptors was upregulated. Although gemcitabine pre-treatment of OC cells did not improve the functionality of HPC-NK cells, importantly, HPC-NK cells and gemcitabine additively killed OC cells in vitro. Similarly, combined HPC-NK cell and gemcitabine treatment additively decreased tumor growth in OC-bearing mice. Collectively, our results indicate that combination therapy of HPC-NK cells and gemcitabine results in augmented OC killing in vitro and in vivo. This provides a rationale for exploring this therapeutic strategy in patients with recurrent OC. [ABSTRACT FROM AUTHOR]- Published
- 2021
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10. Cell composition and expansion strategy can reduce the beneficial effect of AKT-inhibition on functionality of CD8+ T cells.
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Mousset, Charlotte M., Hobo, Willemijn, de Ligt, Aafke, Baardman, Sjoerd, Schaap, Nicolaas P. M., Jansen, Joop H., van der Waart, Anniek B., and Dolstra, Harry
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T cells ,STEM cells ,CELLULAR therapy ,LYMPHOCYTES - Abstract
AKT-inhibition is a promising approach to improve T cell therapies; however, its effect on CD4
+ T cells is insufficiently explored. Previously, we and others showed that AKT-inhibition during ex vivo CD8+ T cell expansion facilitates the generation of polyfunctional T cells with stem cell memory-like traits. However, most therapeutic T cell products are generated from lymphocytes, containing CD4+ T cells that can affect CD8+ T cells dependent on the Th-subset. Here, we investigated the effect of AKT-inhibition on CD4+ T cells, during separate as well as total T cell expansions. Interestingly, ex vivo AKT-inhibition preserved the early memory phenotype of CD4+ T cells based on higher CD62L, CXCR4 and CCR7 expression. However, in the presence of AKT-inhibition, Th-differentiation was skewed toward more Th2-associated at the expense of Th1-associated cells. Importantly, the favorable effect of AKT-inhibition on the functionality of CD8+ T cells drastically diminished in the presence of CD4+ T cells. Moreover, also the expansion method influenced the effect of AKT-inhibition on CD8+ T cells. These findings indicate that the effect of AKT-inhibition on CD8+ T cells is dependent on cell composition and expansion strategy, where presence of CD4+ T cells as well as polyclonal stimulation impede the favorable effect of AKT-inhibition. [ABSTRACT FROM AUTHOR]- Published
- 2020
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11. Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy
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Mousset, Charlotte M., primary, Hobo, Willemijn, additional, Ji, Yun, additional, Fredrix, Hanny, additional, De Giorgi, Valeria, additional, Allison, Robert D., additional, Kester, Michel G. D., additional, Falkenburg, J. H. Frederik, additional, Schaap, Nicolaas P. M., additional, Jansen, Joop H., additional, Gattinoni, Luca, additional, Dolstra, Harry, additional, and van der Waart, Anniek B., additional
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- 2018
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12. Decitabine enhances targeting of AML cells by CD34+ progenitor-derived NK cells in NOD/SCID/IL2Rgnull mice
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Cany, Jeannette, primary, Roeven, Mieke W. H., additional, Hoogstad-van Evert, Janneke S., additional, Hobo, Willemijn, additional, Maas, Frans, additional, Franco Fernandez, Rosalia, additional, Blijlevens, Nicole M. A., additional, van der Velden, Walter J., additional, Huls, Gerwin, additional, Jansen, Joop H., additional, Schaap, Nicolaas P. M., additional, and Dolstra, Harry, additional
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- 2018
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13. Prognostic Value Of Five-Group Cytogenetic Risk Classification In Patients With MDS After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study Of The Chronic Malignancies Working Party Of The EBMT
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Christian Koenecke, Goehring, Gudrun, Wreede, Liesbeth, Biezen, Anja, Scheid, Christof, Volin, Liisa, Maertens, Johan, Finke, Juergen, Schaap, Nicolaas P. M., Robin, Marie, Passweg, Jakob R., Cornelissen, Jan J., Beelen, Dietrich, Heuser, Michael, Witte, Theo, and Kroeger, Nicolaus
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Introduction The only curative treatment approach for patients with myelodysplastic syndromes (MDS) is allogeneic hematopoietic stem cell transplantation (HSCT), but disease relapse after transplantation is a major concern. Predictors for disease outcome after HSCT are limited. However, unfavorable cytogenetic abnormalities have been shown to serve as predictors for MDS-relapse after transplantation. Similar to the data available in MDS-patients not undergoing HSCT (Schanz et al. J Clin Oncol 2012), there is evidence that the novel 5-group cytogenetic classification has a better predictive value for outcome after HSCT than standard IPSS cytogenetics (Deeg et al. Blood 2012). The aim of this large multicentric, international study was to retrospectively determine the impact of the new 5-group cytogenetic MDS classification on outcome after HSCT. Patients and Methods Patients were selected from the EBMT database who had received HSCT for the treatment of MDS between 1982 and 2010 and for whom sufficient cytogenetic information was available. In total, 903 patients were included into the study. At time of HSCT, 97 (10.7%) patients had untreated MDS, 218 (24.1%) patients had advanced MDS or AML evolving from MDS in complete remission, and 227 (25.1%) patients were not in remission after treatment (in 12.3% information on stage of the disease was not available). Median time between diagnosis and transplant was 6.6 months (range 0.2-359.3). Matched related donor HSCT was performed in 574 patients (63.6%), and matched unrelated donor HSCT in 329 patients (36.4%). Bone marrow (35.4%) or peripheral blood (64.6%) served as stem cell graft. Myeloablative preparative regimens were used in 582 patients (64.5%), and a non-myeloablative regimen was given to 320 patients (35.4%). Impact of cytogenetic classification was analyzed in uni- and multivariate models regarding overall survival (OS) and relapse free survival (RFS) after HSCT. Predictive performance of the 2 classifications was compared by means of the cross-validated log partial likelihood. Results Estimated 5-year RFS and OS were 32% and 36% respectively. According to the 5-group cytogenetic classification 19 (2.1%) patients had very good risk cytogenetics, 204 (22.6%) normal risk cytogenetics, 438 (48.5%) intermediate risk cytogenetics, 178 (19.7%) poor risk cytogenetics, and 64 (7.1%) very poor risk cytogenetics. Good, intermediate, and poor risk cytogenetics according to IPSS were found in 192 (38.0%), 500 (40.2%), and 211 (23.7%) patients, respectively. In univariate analysis 5-group cytogenetic information was found to be strongly associated with OS and RFS (OS: log-rank test P Further clinicopathologic factors showed a significant impact on impaired OS and RFS: Disease status at HSCT (RA/RARS no pretreatment; RAEB(t)/sAML in CR; RAEB(t)/sAML not in CR, RAEB(t)/sAML untreated) (OS: P In multivariate analysis, statistically significant predictors for RFS and OS at HSCT were 5-group cytogenetics, IPSS-cytogenetics, disease status and patient's age. Using 5-group cytogenetics classification, patients with poor risk [(RFS: P=.001, HR=1.40 (95% CI: 1.15-1.71); OS: P=.003, HR=1.38 (95% CI: 1.12-1.70)] or very poor risk cytogenetics [(RFS: P When comparing the predictive performance of a series of 3 models both for OS and for RFS – (1) with only classical risk factors, (2) these extended with IPSS cytogenetics, (3) extended with 5-group classification instead-, the model with 5-group cytogenetics performed best. Conclusion In this international, multicentric analysis we confirm that MDS patients with poor and very poor risk cytogenetics had significantly worse RFS and OS after HSCT than patients in the other risk groups of the 5-group cytogenetic classifier. New therapeutic strategies to prevent relapse after HSCT in patients with poor or very poor cytogenetics are urgently needed. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
14. Human secondary lymphoid organs typically contain polyclonally-activated proliferating regulatory T cells
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Peters, Jorieke H., primary, Koenen, Hans J. P. M., additional, Fasse, Esther, additional, Tijssen, Henk J., additional, IJzermans, Jan N. M., additional, Groenen, Patricia J. T. A., additional, Schaap, Nicolaas P. M., additional, Kwekkeboom, Jaap, additional, and Joosten, Irma, additional
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- 2013
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15. Intestinal Damage Determines the Inflammatory Response and Early Complications in Patients Receiving Conditioning for a Stem Cell Transplantation
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van der Velden, Walter J. F. M., primary, Herbers, Alexandra H. E., additional, Feuth, Ton, additional, Schaap, Nicolaas P. M., additional, Donnelly, J. Peter, additional, and Blijlevens, Nicole M. A., additional
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- 2010
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16. Intestinal Damage Determines the Inflammatory Response and Early Complications in Patients Receiving Conditioning for a Stem Cell Transplantation.
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Velden, Walter J. F. M. van der, Herbers, Alexandra H. E., Feuth, Ton, Schaap, Nicolaas P. M., Donnelly, J. Peter, and Blijlevens, Nicole M. A.
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STEM cell transplantation ,CELL transplantation ,FEVER ,NEUTROPENIA ,GRANULOCYTOPENIA ,INTESTINAL diseases ,BACTEREMIA ,BACTERIAL diseases ,BACTERIOLOGY - Abstract
Background: Stem cell transplantation (SCT) is still complicated by the occurrence of fever and inflammatory complications attributed to neutropenia and subsequent infectious complications. The role of mucosal barrier injury (MBI) of the intestinal tract therein has received little attention. Methods: We performed a retrospective analysis in 163 SCT recipients of which data had been collected prospectively on intestinal damage (citrulline), inflammation (C-reactive protein), and neutrophil count. Six different conditioning regimens were studied; 5 myeloablative (MA) and 1 non-myeloablative (NMA). Linear mixed model multivariate and AUC analyses were used to define the role of intestinal damage in post-SCT inflammation. We also studied the relationship between the degree of intestinal damage and the occurrence of early post-SCT complications. Results: In the 5 MA regimen there was a striking pattern of inflammatory response that coincided with the occurrence of severe intestinal damage. This contrasted with a modest inflammatory response seen in the NMA regimen in which intestinal damage was limited. With linear mixed model analysis the degree of intestinal damage was shown the most important determinant of the inflammatory response, and both neutropenia and bacteremia had only a minor impact. AUC analysis revealed a strong correlation between citrulline and CRP (Pearson correlation r = 0.96). Intestinal damage was associated with the occurrence of bacteremia and acute lung injury, and influenced the kinetics of acute graft-versus-host disease. Conclusion: The degree of intestinal damage after myeloablative conditioning appeared to be the most important determined the inflammatory response following SCT, and was associated with inflammatory complications. Studies should explore ways to ameliorate cytotoxic therapy-induced intestinal damage in order to reduce complications associated with myeloablative conditioning therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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17. Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy.
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Mousset, Charlotte M., Hobo, Willemijn, Fredrix, Hanny, Jansen, Joop H., Dolstra, Harry, van der Waart, Anniek B., Ji, Yun, Gattinoni, Luca, De Giorgi, Valeria, Allison, Robert D., Kester, Michel G. D., Falkenburg, J. H. Frederik, and Schaap, Nicolaas P. M.
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T cells ,CANCER ,PATIENTS ,ANTIGENS ,ADENOSINE triphosphatase ,PHENOTYPES ,TRANSCRIPTOMES - Abstract
Adoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivo inhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8
+ T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action. We analyzed phenotype, functionality, metabolism and transcriptome of AKT-inhibited CD8+ T cells using different T cell activation models. Most inhibitors facilitated T cell expansion while preserving an early memory phenotype, reflected by maintenance of CD62L, CCR7 and CXCR4 expression. Moreover, transcriptome profiling revealed that AKT-inhibited CD8+ T cells clustered closely to naturally occurring stem cell-memory CD8+ T cells, while control T cells resembled effector-memory T cells. Interestingly, AKT-inhibited CD8+ T cells showed enrichment of hypoxia-associated genes, which was consistent with enhanced glycolytic function. Notably, AKT-inhibition during MiHA-specific CD8+ T cell priming uncoupled preservation of early memory differentiation from ex vivo expansion. Furthermore, AKT-inhibited MiHA-specific CD8+ T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall. Together, these data demonstrate that AKT-inhibitors with different modality of action promote the ex vivo generation of stem cell memory-like CD8+ T cells with a unique metabolic profile and retained polyfunctionality. Akt-inhibitor VIII and GDC-0068 outperformed other inhibitors, and are therefore promising candidates for ex vivo generation of superior tumor-reactive T cells for adoptive immunotherapy in cancer patients. [ABSTRACT FROM AUTHOR]- Published
- 2018
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18. Ex vivoAKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+T cells for adoptive immunotherapy
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Mousset, Charlotte M., Hobo, Willemijn, Ji, Yun, Fredrix, Hanny, De Giorgi, Valeria, Allison, Robert D., Kester, Michel G. D., Falkenburg, J. H. Frederik, Schaap, Nicolaas P. M., Jansen, Joop H., Gattinoni, Luca, Dolstra, Harry, and van der Waart, Anniek B.
- Abstract
ABSTRACTAdoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivoinhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8+T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action. We analyzed phenotype, functionality, metabolism and transcriptome of AKT-inhibited CD8+T cells using different T cell activation models. Most inhibitors facilitated T cell expansion while preserving an early memory phenotype, reflected by maintenance of CD62L, CCR7 and CXCR4 expression. Moreover, transcriptome profiling revealed that AKT-inhibited CD8+T cells clustered closely to naturally occurring stem cell-memory CD8+T cells, while control T cells resembled effector-memory T cells. Interestingly, AKT-inhibited CD8+T cells showed enrichment of hypoxia-associated genes, which was consistent with enhanced glycolytic function. Notably, AKT-inhibition during MiHA-specific CD8+T cell priming uncoupled preservation of early memory differentiation from ex vivoexpansion. Furthermore, AKT-inhibited MiHA-specific CD8+T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall. Together, these data demonstrate that AKT-inhibitors with different modality of action promote the ex vivogeneration of stem cell memory-like CD8+T cells with a unique metabolic profile and retained polyfunctionality. Akt-inhibitor VIII and GDC-0068 outperformed other inhibitors, and are therefore promising candidates for ex vivogeneration of superior tumor-reactive T cells for adoptive immunotherapy in cancer patients.
- Published
- 2018
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19. Decitabine enhances targeting of AML cells by CD34+ progenitor-derived NK cells in NOD/SCID/IL2Rgnull mice.
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Cany, Jeannette, Roeven, Mieke W. H., Hoogstad-van Evert, Janneke S., Hobo, Willemijn, Maas, Frans, Fernandez, Rosalia Franco, Blijlevens, Nicole M. A., van der Velden, Walter J., Huls, Gerwin, Jansen, Joop H., Schaap, Nicolaas P. M., and Dolstra, Harry
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DECITABINE , *ACUTE myeloid leukemia treatment , *CD34 antigen , *PROGENITOR cells , *KILLER cells , *AZACITIDINE , *HEMATOPOIETIC stem cell transplantation - Abstract
Combining natural killer (NK) cell adoptive transfer with hypomethylating agents (HMAs) is an attractive therapeutic approach for patients with acute myeloid leukemia (AML). However, data regarding the impact of HMAs on NK cell functionality are mostly derived from in vitro studies with high nonclinical relevant drug concentrations. In the present study, we report a comparative study of azacitidine (AZA) and decitabine (DAC) in combination with allogeneic NK cells generated from CD34+ hematopoietic stem and progenitor cells (HSPC-NK cells) in in vitro and in vivo AML models. In vitro, low-dose HMAs did not impair viability of HSPC-NK cells. Furthermore, low-dose DAC preserved HSPC-NK killing, proliferation, and interferon gamma production capacity, whereas AZA diminished their proliferation and reactivity. Importantly, we showed HMAs and HSPC-NK cells could potently work together to target AML cell lines and patient AML blasts. In vivo, both agents exerted a significant delay in AML progression in NOD/SCID/IL2Rgnull mice, but the persistence of adoptively transferred HSPC-NK cells was not affected. Infused NK cells showed sustained expression of most activating receptors, upregulated NKp44 expression, and remarkable killer cell immunoglobulin-like receptor acquisition. Most importantly, only DAC potentiated HSPC-NK cell anti-leukemic activity in vivo. Besides upregulation of NKG2D- and DNAM-1-activating ligands on AML cells, DAC enhanced messenger RNA expression of inflammatory cytokines, perforin, and TRAIL by HSPC-NK cells. In addition, treatment resulted in increased numbers of HSPC-NK cells in the bone marrow compartment, suggesting that DAC could positively modulate NK cell activity, trafficking, and tumor targeting. These data provide a rationale to explore combination therapy of adoptive HSPC-NK cells and DAC in patients with AML. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
20. Engineering of CD34+ progenitor-derived natural killer cells with higher-affinity CD16a for enhanced antibody-dependent cellular cytotoxicity.
- Author
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van Hauten PMM, Hooijmaijers L, Vidal-Manrique M, van der Waart AB, Hobo W, Wu J, Blijlevens NMA, Jansen JH, Walcheck B, Schaap NPM, de Jonge PKJD, and Dolstra H
- Subjects
- Cell Adhesion Molecules metabolism, Cell Line, Tumor, Killer Cells, Natural, Receptors, Fc metabolism, Humans, Antibody-Dependent Cell Cytotoxicity, Receptors, IgG
- Abstract
Background Aims: Natural killer (NK) cell transfer is a promising cellular immunotherapy for cancer. Previously, we developed a robust method to generate large NK cell numbers from CD34
+ hematopoietic stem and progenitor cells (HSPCs), which exhibit strong anti-tumor activity. However, since these cells express low levels of the Fc receptor CD16a in vitro, antibody-dependent cellular cytotoxicity (ADCC) by these cells is limited. To broaden clinical applicability of our HSPC-NK cells toward less NK-sensitive malignancies, we aimed to improve ADCC through CD16a transduction., Methods: Using wildtype and S197P mutant greater-affinity (both with V158) CD16a retroviral transgenes (i.e., a cleavable and noncleavable CD16a upon stimulation), we generated CD16a HSPC-transduced NK cells, with CD34+ cells isolated from umbilical cord blood (UCB) or peripheral blood after G-CSF stem cell mobilization (MPB). CD16a expressing NK cells were enriched using flow cytometry-based cell sorting. Subsequently, phenotypic analyses and functional assays were performed to investigate natural cytotoxicity and ADCC activity., Results: Mean transduction efficiency was 34% for UCB-derived HSPCs and 20% for MPB-derived HSPCs, which was enriched by flow cytometry-based cell sorting to >90% for both conditions. Expression of the transgene remained stable during the entire NK expansion cell generation process. Proliferation and differentiation of HSPCs were not hampered by the transduction process, resulting in effectively differentiated CD56+ NK cells after 5 weeks. Activation of the HSPC-derived NK cells resulted in significant shedding of wildtype CD16a transcribed from the endogenous gene, but not of the noncleavable mutant CD16a protein expressed from the transduced construct. The mean increase of CD107+ IFNγ+ expressing NK cells after inducing ADCC was tenfold in enriched noncleavable CD16a HSPC-NK cells. Killing capacity of CD16a-transduced NK cells was significantly improved after addition of a tumor-targeting antibody in tumor cell lines and primary B-cell leukemia and lymphoma cells compared to unmodified HSPC-NK cells., Conclusions: Together, these data demonstrate that the applicability of adoptive NK cell immunotherapy may be broadened to less NK-sensitive malignancies by upregulation of CD16a expression in combination with the use of tumor-targeting monoclonal antibodies., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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21. Clinically applicable CD34 + -derived blood dendritic cell subsets exhibit key subset-specific features and potently boost anti-tumor T and NK cell responses.
- Author
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van Eck van der Sluijs J, van Ens D, Thordardottir S, Vodegel D, Hermens I, van der Waart AB, Falkenburg JHF, Kester MGD, de Rink I, Heemskerk MHM, Borst J, Schaap NPM, Jansen JH, Xiao Y, Dolstra H, and Hobo W
- Subjects
- Antigen Presentation immunology, Antigens, CD34, Cross-Priming immunology, Humans, Lymphocyte Activation immunology, Cell Culture Techniques methods, Dendritic Cells immunology, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells immunology, Killer Cells, Natural immunology, T-Lymphocytes immunology
- Abstract
Allogeneic stem cell transplantation (alloSCT), following induction chemotherapy, can be curative for hemato-oncology patients due to powerful graft-versus-tumor immunity. However, disease recurrence remains the major cause of treatment failure, emphasizing the need for potent adjuvant immunotherapy. In this regard, dendritic cell (DC) vaccination is highly attractive, as DCs are the key orchestrators of innate and adaptive immunity. Natural DC subsets are postulated to be more powerful compared with monocyte-derived DCs, due to their unique functional properties and cross-talk capacity. Yet, obtaining sufficient numbers of natural DCs, particularly type 1 conventional DCs (cDC1s), is challenging due to low frequencies in human blood. We developed a clinically applicable culture protocol using donor-derived G-CSF mobilized CD34
+ hematopoietic progenitor cells (HPCs) for simultaneous generation of high numbers of cDC1s, cDC2s and plasmacytoid DCs (pDCs). Transcriptomic analyses demonstrated that these ex vivo-generated DCs highly resemble their in vivo blood counterparts. In more detail, we demonstrated that the CD141+ CLEG9A+ cDC1 subset exhibited key features of in vivo cDC1s, reflected by high expression of co-stimulatory molecules and release of IL-12p70 and TNF-α. Furthermore, cDC1s efficiently primed alloreactive T cells, potently cross-presented long-peptides and boosted expansion of minor histocompatibility antigen-experienced T cells. Moreover, they strongly enhanced NK cell activation, degranulation and anti-leukemic reactivity. Together, we developed a robust culture protocol to generate highly functional blood DC subsets for in vivo application as tailored adjuvant immunotherapy to boost innate and adaptive anti-tumor immunity in alloSCT patients., (© 2021. The Author(s).)- Published
- 2021
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22. CD34 + progenitor-derived NK cell and gemcitabine combination therapy increases killing of ovarian cancer cells in NOD/SCID/IL2Rg null mice.
- Author
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Van der Meer JMR, de Jonge PKJD, van der Waart AB, Geerlings AC, Moonen JP, Brummelman J, de Klein J, Vermeulen MC, Maas RJA, Schaap NPM, Hoogstad-van Evert JS, Ottevanger PB, Jansen JH, Hobo W, and Dolstra H
- Subjects
- Animals, Deoxycytidine analogs & derivatives, Female, Humans, Interleukin Receptor Common gamma Subunit, Killer Cells, Natural, Mice, Mice, Inbred NOD, Mice, SCID, Gemcitabine, Neoplasm Recurrence, Local, Ovarian Neoplasms drug therapy
- Abstract
Combining natural killer (NK) cell adoptive transfer with tumor-sensitizing chemotherapy is an attractive approach against recurrent ovarian cancer (OC), as OC is sensitive to NK cell-mediated immunity. Previously, we showed that CD34
+ hematopoietic progenitor cell (HPC)-derived NK cells can kill OC cells in vitro and inhibit OC tumor growth in mice. Here, we investigated the potential of HPC-NK cell therapy combined with chemotherapeutic gemcitabine (used in recurrent OC patients) against OC. We examined the phenotypical, functional, and cytotoxic effects of gemcitabine on HPC-NK cells and/or OC cells in vitro and in OC-bearing mice. To this end, we treated OC cells and/or HPC-NK cells with or without gemcitabine and analyzed the phenotype, cytokine production, and anti-tumor reactivity. We found that gemcitabine did not affect the phenotype and functionality of HPC-NK cells, while on OC cells expression of NK cell activating ligands and death receptors was upregulated. Although gemcitabine pre-treatment of OC cells did not improve the functionality of HPC-NK cells, importantly, HPC-NK cells and gemcitabine additively killed OC cells in vitro . Similarly, combined HPC-NK cell and gemcitabine treatment additively decreased tumor growth in OC-bearing mice. Collectively, our results indicate that combination therapy of HPC-NK cells and gemcitabine results in augmented OC killing in vitro and in vivo . This provides a rationale for exploring this therapeutic strategy in patients with recurrent OC., Competing Interests: None of the authors have any competing interests., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2021
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23. Double Umbilical Cord Blood Transplantation in High-Risk Hematological Patients: A Phase II Study Focusing on the Mechanism of Graft Predominance.
- Author
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Kalin B, Ter Borg M, Wijers R, Somers JAE, van der Holt B, van Bergen CAM, Petersen EJ, Kuball J, Meijer E, Schaap NPM, Zeerleder SS, Broers AE, Braakman E, Falkenburg JHF, Lamers CHJ, and Cornelissen JJ
- Abstract
Competing Interests: The authors declare no conflicts of interest.
- Published
- 2019
- Full Text
- View/download PDF
24. Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid-Refractory Acute Graft-versus-Host Disease.
- Author
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Groth C, van Groningen LFJ, Matos TR, Bremmers ME, Preijers FWMB, Dolstra H, Reicherts C, Schaap NPM, van Hooren EHG, IntHout J, Masereeuw R, Netea MG, Levine JE, Morales G, Ferrara JL, Blijlevens NMA, van Oosterhout YVJM, Stelljes M, and van der Velden WJFM
- Subjects
- Acute Disease, Adolescent, Adult, Aged, Humans, Immunotoxins pharmacology, Middle Aged, Prospective Studies, Young Adult, Graft vs Host Disease drug therapy, Immunotoxins therapeutic use
- Abstract
Effective therapies for treating patients with steroid-refractory acute graft-versus-host-disease (SR-aGVHD), particularly strategies that reduce the duration of immunosuppression following remission, are urgently needed. The investigated immunotoxin combination consists of a mixture of anti-CD3 and anti-CD7 antibodies separately conjugated to recombinant ricin A (CD3/CD7-IT), which induces in vivo depletion of T cells and natural killer (NK) cells and suppresses T cell receptor activation. We conducted a phase I/II trial to examine the safety and efficacy of CD3/CD7-IT in 20 patients with SR-aGVHD; 17 of these patients (85%) had severe SR-aGVHD, and all 20 patients had visceral organ involvement, including 18 (90%) with gastrointestinal (GI) involvement and 5 (25%) with liver involvement. A validated 2-biomarker algorithm classified the majority of patients (11 of 20) as high risk. On day 28 after the start of CD3/CD7-IT therapy, the overall response rate was 60% (12 of 20), with 10 patients (50%) achieving a complete response. The 6-month overall survival rate was 60% (12 of 20), including 64% (7 of 11) classified as high risk by biomarkers. The 1-week course of treatment with CD3/CD7-IT caused profound but transient depletion of T cells and NK cells, followed by rapid recovery of the immune system with a diverse TCR Vβ repertoire, and preservation of Epstein-Barr virus- and cytomegalovirus-specific T cell clones. Furthermore, our results indicate that CD3/CD7-IT appeared to be safe and well tolerated, with a relatively low prevalence of manageable and reversible adverse events, primarily worsening of hypoalbuminemia, microangiopathy, and thrombocytopenia. These encouraging results suggest that CD3/CD7-IT may improve patient outcomes in patients with SR-aGVHD., (Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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25. Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8 + T cells for adoptive immunotherapy.
- Author
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Mousset CM, Hobo W, Ji Y, Fredrix H, De Giorgi V, Allison RD, Kester MGD, Falkenburg JHF, Schaap NPM, Jansen JH, Gattinoni L, Dolstra H, and van der Waart AB
- Abstract
Adoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivo inhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8
+ T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action. We analyzed phenotype, functionality, metabolism and transcriptome of AKT-inhibited CD8+ T cells using different T cell activation models. Most inhibitors facilitated T cell expansion while preserving an early memory phenotype, reflected by maintenance of CD62L, CCR7 and CXCR4 expression. Moreover, transcriptome profiling revealed that AKT-inhibited CD8+ T cells clustered closely to naturally occurring stem cell-memory CD8+ T cells, while control T cells resembled effector-memory T cells. Interestingly, AKT-inhibited CD8+ T cells showed enrichment of hypoxia-associated genes, which was consistent with enhanced glycolytic function. Notably, AKT-inhibition during MiHA-specific CD8+ T cell priming uncoupled preservation of early memory differentiation from ex vivo expansion. Furthermore, AKT-inhibited MiHA-specific CD8+ T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall. Together, these data demonstrate that AKT-inhibitors with different modality of action promote the ex vivo generation of stem cell memory-like CD8+ T cells with a unique metabolic profile and retained polyfunctionality. Akt-inhibitor VIII and GDC-0068 outperformed other inhibitors, and are therefore promising candidates for ex vivo generation of superior tumor-reactive T cells for adoptive immunotherapy in cancer patients.- Published
- 2018
- Full Text
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26. Decitabine enhances targeting of AML cells by CD34 + progenitor-derived NK cells in NOD/SCID/IL2Rg null mice.
- Author
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Cany J, Roeven MWH, Hoogstad-van Evert JS, Hobo W, Maas F, Franco Fernandez R, Blijlevens NMA, van der Velden WJ, Huls G, Jansen JH, Schaap NPM, and Dolstra H
- Subjects
- Animals, Antigens, CD34 analysis, Cells, Cultured, Gene Deletion, Humans, Interleukin Receptor Common gamma Subunit genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Mice, Inbred NOD, Mice, SCID, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, Decitabine therapeutic use, Immunotherapy, Adoptive methods, Killer Cells, Natural transplantation, Leukemia, Myeloid, Acute therapy
- Abstract
Combining natural killer (NK) cell adoptive transfer with hypomethylating agents (HMAs) is an attractive therapeutic approach for patients with acute myeloid leukemia (AML). However, data regarding the impact of HMAs on NK cell functionality are mostly derived from in vitro studies with high nonclinical relevant drug concentrations. In the present study, we report a comparative study of azacitidine (AZA) and decitabine (DAC) in combination with allogeneic NK cells generated from CD34
+ hematopoietic stem and progenitor cells (HSPC-NK cells) in in vitro and in vivo AML models. In vitro, low-dose HMAs did not impair viability of HSPC-NK cells. Furthermore, low-dose DAC preserved HSPC-NK killing, proliferation, and interferon gamma production capacity, whereas AZA diminished their proliferation and reactivity. Importantly, we showed HMAs and HSPC-NK cells could potently work together to target AML cell lines and patient AML blasts. In vivo, both agents exerted a significant delay in AML progression in NOD/SCID/IL2Rgnull mice, but the persistence of adoptively transferred HSPC-NK cells was not affected. Infused NK cells showed sustained expression of most activating receptors, upregulated NKp44 expression, and remarkable killer cell immunoglobulin-like receptor acquisition. Most importantly, only DAC potentiated HSPC-NK cell anti-leukemic activity in vivo. Besides upregulation of NKG2D- and DNAM-1-activating ligands on AML cells, DAC enhanced messenger RNA expression of inflammatory cytokines, perforin, and TRAIL by HSPC-NK cells. In addition, treatment resulted in increased numbers of HSPC-NK cells in the bone marrow compartment, suggesting that DAC could positively modulate NK cell activity, trafficking, and tumor targeting. These data provide a rationale to explore combination therapy of adoptive HSPC-NK cells and DAC in patients with AML., (© 2018 by The American Society of Hematology.)- Published
- 2018
- Full Text
- View/download PDF
27. Addition of 10-Day Decitabine to Fludarabine/Total Body Irradiation Conditioning is Feasible and Induces Tumor-Associated Antigen-Specific T Cell Responses.
- Author
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Cruijsen M, Hobo W, van der Velden WJFM, Bremmers MEJ, Woestenenk R, Bär B, Falkenburg JHF, Kester M, Schaap NPM, Jansen J, Blijlevens NNM, Dolstra H, and Huls G
- Subjects
- Adult, Aged, Antigens, Neoplasm immunology, Antimetabolites, Antineoplastic administration & dosage, Azacitidine administration & dosage, Azacitidine pharmacology, CD8-Positive T-Lymphocytes drug effects, Decitabine, Female, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cell Transplantation mortality, Humans, Leukemia, Myeloid, Acute mortality, Leukemia, Myelomonocytic, Chronic mortality, Male, Middle Aged, Myelodysplastic Syndromes mortality, Survival Analysis, Transplantation Conditioning adverse effects, Transplantation, Homologous, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Whole-Body Irradiation, Azacitidine analogs & derivatives, CD8-Positive T-Lymphocytes immunology, Leukemia, Myeloid, Acute therapy, Leukemia, Myelomonocytic, Chronic therapy, Myelodysplastic Syndromes therapy, Transplantation Conditioning methods
- Abstract
Allogeneic hematopoietic cell transplantation (HCT) offers the possibility of curative therapy for patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myelogenous leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics and in patients who cannot tolerate consolidation chemotherapy (eg, due to previous toxicity). We assessed the toxicity and efficacy of 10-day decitabine (Dec), fludarabine (Flu), and 2 Gy total body irradiation (TBI) as a new conditioning regimen for allogeneic HCT in patients with MDS, CMML, or AML. Thirty patients were enrolled, including 11 with MDS, 2 with CMML, and 17 with AML. Patients received 20 mg/m(2)/day Dec on days -11 to -2, 30 mg/m(2)/day Flu on days -4 to -2, and 2 Gy TBI on day -1, followed by infusion of a donor stem cell graft on day 0. Postgrafting immunosuppression consisted of cyclosporin A and mycophenolate mofetil. At a median follow-up of 443 days, the overall survival was 53%, relapse incidence was 27%, and nonrelapse mortality was 27%. The incidence of severe acute (grade III/IV) graft-versus-host disease (GVHD) was 27%, and that of (predominantly mild) chronic GVHD was 60%. Immunomonitoring studies revealed that specific CD8(+) T cell responses against epigenetically silenced tumor-associated antigens (TAAs), including cancer-testis antigens (MAGE-A1/A2/A3 and PRAME) and RHAMM, occurred more frequently in patients who had received Dec/Flu/TBI conditioning (8 of 11 patients) compared with a control group of patients who had received only Flu/TBI conditioning (2 of 9 patients). In summary, Dec/Flu/TBI conditioning proved feasible and effective and enhanced the induction of TAA-reactive CD8(+) T cell responses in vivo, which may contribute to disease control post-transplantation., (Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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- View/download PDF
28. Combination Therapy with Inolimomab and Etanercept for Severe Steroid-Refractory Acute Graft-versus-Host Disease.
- Author
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van Groningen LF, Liefferink AM, de Haan AF, Schaap NP, Donnelly JP, Blijlevens NM, and van der Velden WJ
- Subjects
- Acute Disease, Adult, Aged, Allografts, Disease-Free Survival, Drug Therapy, Combination methods, Female, Humans, Male, Middle Aged, Stem Cell Transplantation, Steroids administration & dosage, Survival Rate, Antibodies, Monoclonal administration & dosage, Drug Resistance drug effects, Etanercept administration & dosage, Graft vs Host Disease drug therapy, Graft vs Host Disease etiology, Graft vs Host Disease mortality, Hematologic Neoplasms mortality, Hematologic Neoplasms therapy
- Abstract
Steroid-refractory acute graft-versus-host disease (aGVHD) remains an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). A protocol on the management of aGVHD was introduced in our center that incorporated a prospective study on combination therapy with inolimomab (anti-IL-2Rα) and etanercept (anti-tumor necrosis factor-α) for steroid-refractory aGVHD. We evaluated the efficacy and safety in 21 consecutively treated patients. The patients had developed refractory aGVHD after SCT (n = 16) or donor lymphocyte infusion (n = 5), and aGVHD was classified as severe in all patients, mostly due to gastrointestinal involvement stages 2 to 4. No drug-related side effects were observed apart from the infections expected to occur in these severely immunocompromised patients. Overall response at day 28 of second-line therapy was 48% (10/21), with 6 and 4 patients achieving a complete and partial response, respectively. Eventually, 19 patients died (90%), with early mortality (<6 months) predominantly resulting from refractory aGVHD and secondary infections and late mortality resulting from relapse of the underlying disease. With a median follow-up of 55 days, the estimated rates of 6-month and 2-year overall survival were dismal, 29% and 10%, respectively. In conclusion, the combination of inolimomab and etanercept for steroid-refractory aGVHD failed to improve the dismal prognosis of severe steroid-refractory aGVHD., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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29. Early administration of donor lymphocyte infusions upon molecular relapse after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia: a study by the Chronic Malignancies Working Party of the EBMT.
- Author
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Chalandon Y, Passweg JR, Guglielmi C, Iacobelli S, Apperley J, Schaap NP, Finke J, Robin M, Fedele R, Bron D, Yakoub-Agha I, van Biezen A, de Witte T, Kröger N, and Olavarria E
- Subjects
- Disease Progression, Female, Follow-Up Studies, Graft vs Host Disease immunology, Graft vs Host Disease mortality, Graft vs Host Disease pathology, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Neoplasm, Residual immunology, Neoplasm, Residual mortality, Neoplasm, Residual pathology, Recurrence, Siblings, Survival Analysis, Time Factors, Transplantation, Homologous, Unrelated Donors, Graft vs Host Disease therapy, Hematopoietic Stem Cell Transplantation, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Lymphocyte Transfusion, Neoplasm, Residual therapy
- Abstract
Patients with chronic myeloid leukemia relapsing after allogeneic hematopoietic stem cell transplantation may be treated by tyrosine kinase inhibitors and/or by donor lymphocyte infusions. The best strategies and timing of administration of lymphocytes are unclear. We analyzed 155 patients who relapsed after allogeneic stem cell transplantation with disease detectable only by molecular methods and who subsequently received lymphocytes. Transplants were performed in first chronic phase (n=125) or in advanced disease (n=29) from identical siblings (n=84) or unrelated donors (n=71) between 1986 and 2003. They received lymphocytes either during molecular relapse (n=85) or upon progression to more advanced disease (1993 to 2004). The median interval from relapse to lymphocyte infusion was 210 (0-1673) days. The median follow up after it was 46 (3-135) months. Overall survival was 76±4% at five years after lymphocyte infusions (89±8% with sibling donors and 63±13% with unrelated donors (P=0.003)). Survival was 69±14% when lymphocytes were given within six months of the detection of molecular relapse and 81±10% (P=0.061) when given later; 81±11% if given at molecular relapse versus 71±12% (P=0.26) with more advanced disease. In multivariate analysis survival was worse if the donor was unrelated (HR 2.54 (95% CI: 1.15-5.53), P=0.021) and better with lymphocyte infusions beyond six months from molecular relapse (HR 0.4 (95%CI: 0.19-0.84), P=0.018). These data confirm the remarkable efficacy of lymphocyte infusions for this disease. There appears to be no advantage from administering it early upon detection of molecular relapse in patients who received allogeneic stem cell transplantation for chronic myeloid leukemia., (Copyright© Ferrata Storti Foundation.)
- Published
- 2014
- Full Text
- View/download PDF
30. Polymorphisms in CCR6 are associated with chronic graft-versus-host disease and invasive fungal disease in matched-related hematopoietic stem cell transplantation.
- Author
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Broen K, van der Waart AB, Greupink-Draaisma A, Metzig J, Feuth T, Schaap NP, Blijlevens NM, van der Velden WJ, and Dolstra H
- Subjects
- Adult, Alleles, Chronic Disease, Genotype, Graft vs Host Disease immunology, Hematologic Neoplasms genetics, Hematologic Neoplasms immunology, Hematologic Neoplasms therapy, Humans, Immunity, Cellular genetics, Immunity, Cellular immunology, Male, Middle Aged, Mycoses immunology, Netherlands, Receptors, CCR6 immunology, Receptors, Interleukin genetics, Receptors, Interleukin immunology, T-Lymphocytes immunology, Transplantation, Homologous, Graft vs Host Disease genetics, Hematopoietic Stem Cell Transplantation, Mycoses genetics, Polymorphism, Single Nucleotide, Receptors, CCR6 genetics, Unrelated Donors
- Abstract
Graft-versus-host disease (GVHD) and fungal infections are frequent complications after allogeneic hematopoietic stem cell transplantation (HSCT). Single nucleotide polymorphisms (SNPs) in genes of the immune system can influence the inflammatory cascade and T cell-driven alloimmune reactions after HSCT, and thus increasing the incidence of GVHD and infectious complications. Here, we investigated the effect of SNPs in IL-23R and CCR6 on posttransplantation outcome in 161 recipients of partially T cell-depleted HSCT. Remarkably, IL-23R SNPs were not associated with clinical outcome, but we found that disparities in the CCR6 tagSNP rs2301436 and SNP rs3093023 are independently associated with the occurrence of chronic GVHD (cGVHD) and invasive fungal disease. In multivariate analysis, patients receiving a transplant from a homozygous rs2301436 G allele donor showed less cGVHD (odds ratio [OR]: 0.16; P = .002), as was the case for a homozygous donor rs3093023 G allele (OR: 0.24; P = .005). In parallel, the GG genotype at rs2301436 in donors was associated with a higher incidence of invasive fungal disease at day 100 after HSCT (OR: 3.59; P = .008). This study shows that CCR6 SNPs can be used to predict clinical outcome, and that polymorphisms in the CCR6 gene may influence T cell-mediated immune reactions after HSCT., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
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