40 results on '"Schaap, Nicolaas P. M."'
Search Results
2. Low relapse risk in poor risk AML after conditioning with 10-day decitabine, fludarabine and 2 Gray TBI prior to allogeneic hematopoietic cell transplantation
- Author
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Cruijsen, Marjan, Hilberink, Jacobien R., van der Velden, Walter J. F. M., Jansen, Joop H., Bär, Brigitte, Schaap, Nicolaas P. M., de Haan, Anton, Mulder, André B., de Groot, Marco R., Baron, Frédéric, Vellenga, Edo, Blijlevens, Nicole N. M., and Huls, Gerwin
- Published
- 2021
- Full Text
- View/download PDF
3. Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party
- Author
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Bazarbachi, Abdul Hamid, Al Hamed, Rama, Labopin, Myriam, Halaburda, Kazimierz, Labussiere, Helene, Bernasconi, Paolo, Schroyens, Wilfried, Gandemer, Virginie, Schaap, Nicolaas P. M., Loschi, Michael, Jindra, Pavel, Snowden, John, Wu, Depei, Guffroy, Blandine, Rovira, Montserrat, Chantepie, Sylvain P., Poiré, Xavier, Lopez-Corral, Lucia, Nikolousis, Manos, Pelosini, Matteo, Ciceri, Fabio, Baron, Frederic, Bazarbachi, Ali, Corbacioglu, Selim, Savani, Bipin N., Peric, Zinaida, Nagler, Arnon, Carreras, Enric, and Mohty, Mohamad
- Published
- 2021
- Full Text
- View/download PDF
4. Endothelial Activation and Stress Index (EASIX) to predict mortality after allogeneic stem cell transplantation: a prospective study
- Author
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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
- Published
- 2024
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5. PD-L1 siRNA-mediated silencing in acute myeloid leukemia enhances anti-leukemic T cell reactivity
- Author
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van Ens, Diede, Mousset, Charlotte M., Hutten, Tim J. A., van der Waart, Anniek B., Campillo-Davo, Diana, van der Heijden, Sanne, Vodegel, Denise, Fredrix, Hanny, Woestenenk, Rob, Parga-Vidal, Loreto, Jansen, Joop H., Schaap, Nicolaas P. M., Lion, Eva, Dolstra, Harry, and Hobo, Willemijn
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- 2020
- Full Text
- View/download PDF
6. Cell composition and expansion strategy can reduce the beneficial effect of AKT-inhibition on functionality of CD8+ T cells
- Author
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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
- Published
- 2020
- Full Text
- View/download PDF
7. Allogeneic Stem Cell Transplantation in Patients >40 Years of Age With Acute Lymphoblastic Leukemia: Reduced Intensity Versus Myeloablative Conditioning
- Author
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MS Hematologie, Cancer, Infection & Immunity, Sijs-Szabo, Aniko, Dinmohamed, Avinash G, Versluis, Jurjen, van der Holt, Bronno, Bellido, Mar, Hazenberg, Mette D, van Gelder, Michel, Schaap, Nicolaas P M, Meijer, Ellen, van der Wagen, Lotte E, Halkes, Constantijn J M, Rijneveld, Anita W, Cornelissen, Jan J, MS Hematologie, Cancer, Infection & Immunity, Sijs-Szabo, Aniko, Dinmohamed, Avinash G, Versluis, Jurjen, van der Holt, Bronno, Bellido, Mar, Hazenberg, Mette D, van Gelder, Michel, Schaap, Nicolaas P M, Meijer, Ellen, van der Wagen, Lotte E, Halkes, Constantijn J M, Rijneveld, Anita W, and Cornelissen, Jan J
- Published
- 2023
8. 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.
- Author
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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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9. 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
- Published
- 2022
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10. 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
- 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.
- Published
- 2021
11. Thiotepa-based versus total body irradiation-based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission: a retrospective analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation
- Author
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Eder, Sandra, Labopin, Myriam, Arcese, William, Or, Reuven, Majolino, Ignazio, Bacigalupo, Andrea, de Rosa, Gennaro, Volin, Liisa, Beelen, Dietrich, Veelken, Hendrik, Schaap, Nicolaas P. M., Kuball, Jurgen, Cornelissen, Jan, Nagler, Arnon, and Mohty, Mohamad
- Published
- 2016
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12. Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party.
- Author
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UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre du cancer, UCL - (SLuc) Service d'hématologie, Bazarbachi, Abdul Hamid, Al Hamed, Rama, Labopin, Myriam, Halaburda, Kazimierz, Labussiere, Helene, Bernasconi, Paolo, Schroyens, Wilfried, Gandemer, Virginie, Schaap, Nicolaas P M, Loschi, Michael, Jindra, Pavel, Snowden, John, Wu, Depei, Guffroy, Blandine, Rovira, Montserrat, Chantepie, Sylvain P, Poiré, Xavier, Lopez-Corral, Lucia, Nikolousis, Manos, Pelosini, Matteo, Ciceri, Fabio, Baron, Frederic, Bazarbachi, Ali, Corbacioglu, Selim, Savani, Bipin N, Peric, Zinaida, Nagler, Arnon, Carreras, Enric, Mohty, Mohamad, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre du cancer, UCL - (SLuc) Service d'hématologie, Bazarbachi, Abdul Hamid, Al Hamed, Rama, Labopin, Myriam, Halaburda, Kazimierz, Labussiere, Helene, Bernasconi, Paolo, Schroyens, Wilfried, Gandemer, Virginie, Schaap, Nicolaas P M, Loschi, Michael, Jindra, Pavel, Snowden, John, Wu, Depei, Guffroy, Blandine, Rovira, Montserrat, Chantepie, Sylvain P, Poiré, Xavier, Lopez-Corral, Lucia, Nikolousis, Manos, Pelosini, Matteo, Ciceri, Fabio, Baron, Frederic, Bazarbachi, Ali, Corbacioglu, Selim, Savani, Bipin N, Peric, Zinaida, Nagler, Arnon, Carreras, Enric, and Mohty, Mohamad
- Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is a complex, potentially fatal therapy featuring a myriad of complications. Triggering event(s) of such complications vary significantly, but often a so-called "multi-organ failure" (MOF) is reported as the leading cause of death. The identification of the exact trigger of MOF is critical towards early and disease-specific intervention to improve outcome. We examined data from 202 alloHCT patients reported to have died of MOF from the EBMT registry aiming to determine their exact cause of death focusing on veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) due to its life-threatening, often difficult to capture yet preventable nature. We identified a total of 70 patients (35%) for whom VOD/SOS could be considered as trigger for MOF and leading cause of death, among which 48 (69%) were previously undiagnosed. Multivariate analysis highlighted history of hepatic comorbidity or gentuzumab use and disease status beyond CR1 as the only significant factors predictive of VOD/SOS incidence (OR = 6.6; p = 0.001 and OR = 3.3; p = 0.004 respectively). VOD/SOS-related MOF was widely under-reported, accounting for 27% of deaths attributed to MOF of unknown origin without a previous VOD/SOS diagnosis. Our results suggest most missed cases developed late VOD/SOS beyond 21 days post-alloHCT, highlighting the importance of the newly revised EBMT criteria.
- Published
- 2021
13. Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party
- Author
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Bazarbachi, Abdul Hamid, primary, Al Hamed, Rama, additional, Labopin, Myriam, additional, Halaburda, Kazimierz, additional, Labussiere, Helene, additional, Bernasconi, Paolo, additional, Schroyens, Wilfried, additional, Gandemer, Virginie, additional, Schaap, Nicolaas P. M., additional, Loschi, Michael, additional, Jindra, Pavel, additional, Snowden, John, additional, Wu, Depei, additional, Guffroy, Blandine, additional, Rovira, Montserrat, additional, Chantepie, Sylvain P., additional, Poiré, Xavier, additional, Lopez-Corral, Lucia, additional, Nikolousis, Manos, additional, Pelosini, Matteo, additional, Ciceri, Fabio, additional, Baron, Frederic, additional, Bazarbachi, Ali, additional, Corbacioglu, Selim, additional, Savani, Bipin N., additional, Peric, Zinaida, additional, Nagler, Arnon, additional, Carreras, Enric, additional, and Mohty, Mohamad, additional
- Published
- 2020
- Full Text
- View/download PDF
14. 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
- Subjects
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
- Full Text
- View/download PDF
15. 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, 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
- Subjects
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
16. 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, Burak, Ter Borg, Mariëtte, Wijers, Rebecca, Somers, Judith A E, van der Holt, Bronno, van Bergen, Cornelis A M, Petersen, Eefke J, Kuball, Jurgen, Meijer, Ellen, Schaap, Nicolaas P M, Zeerleder, Sacha S, Broers, Annoek E, Braakman, Eric, Falkenburg, J H Frederik, Lamers, Cor H J, Cornelissen, Jan J, Kalin, Burak, Ter Borg, Mariëtte, Wijers, Rebecca, Somers, Judith A E, van der Holt, Bronno, van Bergen, Cornelis A M, Petersen, Eefke J, Kuball, Jurgen, Meijer, Ellen, Schaap, Nicolaas P M, Zeerleder, Sacha S, Broers, Annoek E, Braakman, Eric, Falkenburg, J H Frederik, Lamers, Cor H J, and Cornelissen, Jan J
- Published
- 2019
17. Phase I/II trial of a combination of anti-CD3/CD7 immunotoxins for steroid-refractory acute graft-versus-host disease
- Author
-
Afd Pharmacology, Pharmacology, 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, 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, and van der Velden, Walter J F M
- Published
- 2019
18. 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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MS Hematologie, Regenerative Medicine and Stem Cells, Cancer, CTI Kuball, Infection & Immunity, Kalin, Burak, Ter Borg, Mariëtte, Wijers, Rebecca, Somers, Judith A E, van der Holt, Bronno, van Bergen, Cornelis A M, Petersen, Eefke J, Kuball, Jurgen, Meijer, Ellen, Schaap, Nicolaas P M, Zeerleder, Sacha S, Broers, Annoek E, Braakman, Eric, Falkenburg, J H Frederik, Lamers, Cor H J, Cornelissen, Jan J, MS Hematologie, Regenerative Medicine and Stem Cells, Cancer, CTI Kuball, Infection & Immunity, Kalin, Burak, Ter Borg, Mariëtte, Wijers, Rebecca, Somers, Judith A E, van der Holt, Bronno, van Bergen, Cornelis A M, Petersen, Eefke J, Kuball, Jurgen, Meijer, Ellen, Schaap, Nicolaas P M, Zeerleder, Sacha S, Broers, Annoek E, Braakman, Eric, Falkenburg, J H Frederik, Lamers, Cor H J, and Cornelissen, Jan J
- Published
- 2019
19. CD34+ progenitor-derived NK cell and gemcitabine combination therapy increases killing of ovarian cancer cells in NOD/SCID/IL2Rgnull mice.
- Author
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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
- Subjects
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
- Full Text
- View/download PDF
20. Cell composition and expansion strategy can reduce the beneficial effect of AKT-inhibition on functionality of CD8+ T cells.
- Author
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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
- Subjects
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
- Full Text
- View/download PDF
21. Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy
- Author
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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
- Published
- 2018
- Full Text
- View/download PDF
22. Decitabine enhances targeting of AML cells by CD34+ progenitor-derived NK cells in NOD/SCID/IL2Rgnull mice
- Author
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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
- Published
- 2018
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23. Immune checkpoint molecules in acute myeloid leukaemia: managing the double‐edged sword
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Hobo, Willemijn, primary, Hutten, Tim J. A., additional, Schaap, Nicolaas P. M., additional, and Dolstra, Harry, additional
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- 2018
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24. Thiotepa-based versus total body irradiation-based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission: a retrospective analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation
- Author
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CTI Kuball, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Eder, Sandra, Labopin, Myriam, Arcese, William, Or, Reuven, Majolino, Ignazio, Bacigalupo, Andrea, de Rosa, Gennaro, Volin, Liisa, Beelen, Dietrich, Veelken, Hendrik, Schaap, Nicolaas P M, Kuball, Jurgen, Cornelissen, Jan, Nagler, Arnon, Mohty, Mohamad, Acute Leukemia Working Party, CTI Kuball, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Eder, Sandra, Labopin, Myriam, Arcese, William, Or, Reuven, Majolino, Ignazio, Bacigalupo, Andrea, de Rosa, Gennaro, Volin, Liisa, Beelen, Dietrich, Veelken, Hendrik, Schaap, Nicolaas P M, Kuball, Jurgen, Cornelissen, Jan, Nagler, Arnon, Mohty, Mohamad, and Acute Leukemia Working Party
- Published
- 2016
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, 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.
- Subjects
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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26. Ex vivoAKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+T cells for adoptive immunotherapy
- Author
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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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27. Decitabine enhances targeting of AML cells by CD34+ progenitor-derived NK cells in NOD/SCID/IL2Rgnull mice.
- Author
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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
- Subjects
- *
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
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28. Increased peritoneal TGF-β1 is associated with ascites-induced NK-cell dysfunction and reduced survival in high-grade epithelial ovarian cancer.
- Author
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Maas RJA, Hoogstad-van Evert JS, Hagemans IM, Brummelman J, van Ens D, de Jonge PKJD, Hooijmaijers L, Mahajan S, van der Waart AB, Hermans CKJC, de Klein J, Woestenenk R, van Herwaarden AE, Schaap NPM, Rezaeifard S, Tauriello DVF, Zusterzeel PLM, Ottevanger N, Jansen JH, Hobo W, and Dolstra H
- Subjects
- Humans, Female, Middle Aged, Neoplasm Grading, Aged, Pyrazoles therapeutic use, Pyrazoles pharmacology, Quinolines, Transforming Growth Factor beta1 metabolism, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Carcinoma, Ovarian Epithelial immunology, Carcinoma, Ovarian Epithelial mortality, Ascites immunology, Ovarian Neoplasms immunology, Ovarian Neoplasms mortality, Ovarian Neoplasms pathology
- Abstract
Natural killer (NK) cell therapy represents an attractive immunotherapy approach against recurrent epithelial ovarian cancer (EOC), as EOC is sensitive to NK cell-mediated cytotoxicity. However, NK cell antitumor activity is dampened by suppressive factors in EOC patient ascites. Here, we integrated functional assays, soluble factor analysis, high-dimensional flow cytometry cellular component data and clinical parameters of advanced EOC patients to study the mechanisms of ascites-induced inhibition of NK cells. Using a suppression assay, we found that ascites from EOC patients strongly inhibits peripheral blood-derived NK cells and CD34+ progenitor-derived NK cells, albeit the latter were more resistant. Interestingly, we found that higher ascites-induced NK cell inhibition correlated with reduced progression-free and overall survival in EOC patients. Furthermore, we identified transforming growth factor (TGF)-β1 to correlate with ascites-induced NK cell dysfunction and reduced patient survival. In functional assays, we showed that proliferation and anti-tumor reactivity of CD34+ progenitor-derived NK cells are significantly affected by TGF-β1 exposure. Moreover, inhibition of TGF-β1 signaling with galunisertib partly restored NK cell functionality in some donors. For the cellular components, we showed that the secretome is associated with a different composition of CD45+ cells between ascites of EOC and benign reference samples with higher proportions of macrophages in the EOC patient samples. Furthermore, we revealed that higher TGF-β1 levels are associated with the presence of M2-like macrophages, B cell populations and T-regulatory cells in EOC patient ascites. These findings reveal that targeting TGF-β1 signaling could increase NK cell immune responses in high-grade EOC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Maas, Hoogstad-van Evert, Hagemans, Brummelman, van Ens, de Jonge, Hooijmaijers, Mahajan, van der Waart, Hermans, de Klein, Woestenenk, van Herwaarden, Schaap, Rezaeifard, Tauriello, Zusterzeel, Ottevanger, Jansen, Hobo and Dolstra.)
- Published
- 2024
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29. 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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30. Allogeneic Stem Cell Transplantation in Patients >40 Years of Age With Acute Lymphoblastic Leukemia: Reduced Intensity Versus Myeloablative Conditioning.
- Author
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Sijs-Szabo A, Dinmohamed AG, Versluis J, van der Holt B, Bellido M, Hazenberg MD, van Gelder M, Schaap NPM, Meijer E, van der Wagen LE, Halkes CJM, Rijneveld AW, and Cornelissen JJ
- Subjects
- Humans, Aged, Adult, Retrospective Studies, Recurrence, Transplantation Conditioning adverse effects, Transplantation Conditioning methods, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Leukemia, Myeloid, Acute
- Abstract
Background: The outcome in older patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory due to high relapse and nonrelapse mortality (NRM) rates. Allogeneic stem cell transplantation (alloHSCT) as postremission therapy has an important role in reducing relapse rate, albeit its application is limited in older adult patients due to alloHSCT-related morbidity and mortality. Reduced-intensity conditioning (RIC) alloHSCT has been developed as a less toxic conditioning regimen, but comparative studies with myeloablative conditioning (MAC) are limited in patients with ALL., Methods: In this retrospective study, RIC-alloHSCT (n = 111) was compared with MAC-alloHSCT (n = 77) in patients aged 41 to 65 y with ALL in first complete remission. MAC was predominantly applied by combining high-dose total body irradiation and cyclophosphamide, whereas RIC mainly consisted of fludarabine and 2 Gy total body irradiation., Results: Unadjusted overall survival was 54% (95% confidence interval [CI], 42%-65%) at 5 y in MAC recipients compared with 39% (95% CI, 29%-49%) in RIC recipients. Overall survival and relapse-free survival were not significantly associated with type of conditioning after adjusted for the covariates age, leukemia risk status at diagnosis, donor type, and donor and recipient gender combination. NRM was significantly lower after RIC (subdistribution hazard ratio: 0.41, 95% CI, 0.22-0.78; P = 0.006), whereas relapse was significantly higher (subdistribution hazard ratio: 3.04, 95% CI, 1.71-5.40; P < 0.001)., Conclusions: Collectively, RIC-alloHSCT has resulted in less NRM, but it was also found to be associated with a significantly higher relapse rate. These results suggest that MAC-alloHSCT may provide a more effective type of consolidation therapy for the reduction of relapse and that RIC-alloHSCT may be restricted to patients at higher risk for NRM., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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31. Additional cytogenetic features determine outcome in patients allografted for TP53 mutant acute myeloid leukemia.
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Loke J, Labopin M, Craddock C, Cornelissen JJ, Labussière-Wallet H, Wagner-Drouet EM, Van Gorkom G, Schaap NPM, Kröger NM, Veelken JH, Rovira M, Menard AL, Bug G, Bazarbachi A, Giebel S, Brissot E, Nagler A, Esteve J, and Mohty M
- Subjects
- Chromosome Deletion, Cytogenetic Analysis, Cytogenetics, Humans, Prognosis, Retrospective Studies, Transplantation, Homologous, Tumor Suppressor Protein p53 genetics, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
- Abstract
Background: The presence of TP53 mutations is associated with an unfavorable outcome in patients allografted for acute myeloid leukemia (AML), leading some to question the benefit of an allogeneic stem cell transplantation (allo-SCT) for this patient group, although this has not been studied in a large cohort., Methods: A total of 780 patients with AML in first complete remission, with either intermediate- or adverse-risk cytogenetics, whose TP53 mutation status was reported, were included in this study from the European Society for Blood and Marrow Transplantation., Results: Two-year overall survival (OS) was impaired in patients (n = 179) with evidence of a TP53 mutation at diagnosis (35.1%; 95% confidence interval [CI], 26.7-43.7) as compared to the cohort without (n = 601) (64%; 95% CI, 59.1-68.4; P = .001). In patients with mutant TP53 AML with no evidence of either chromosome 17p loss (17p-) and/or complex karyotype (CK) (n = 53, 29.6%), 2-year OS was 65.2% (95% CI, 48.4-77.6). This was not significantly different to patients without TP53 mutations. In patients with mutant TP53 AML with either 17p- and/or CK (n = 126, 70.4%), the OS was lower (24.6%; 95% CI, 16.2-34; P = .001)., Conclusions: In summary, the adverse prognostic effect of TP53 mutations in AML following an allo-SCT is not evident in patients with neither co-occurring 17p- and/or CK, and these data inform decisions regarding allo-SCT in patients with TP53 mutant AML., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
- Published
- 2022
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32. 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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33. 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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34. 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
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35. 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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36. Single-Dose Daily Fractionation Is Not Inferior to Twice-a-Day Fractionated Total-Body Irradiation Before Allogeneic Stem Cell Transplantation for Acute Leukemia: A Useful Practice Simplification Resulting From the SARASIN Study.
- Author
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Belkacemi Y, Labopin M, Giebel S, Loganadane G, Miszczyk L, Michallet M, Socié G, Schaap NPM, Cornelissen JJ, Yakoub-Agha I, Polge E, Mohty M, Gorin NC, and Nagler A
- Subjects
- Adolescent, Adult, Databases, Factual, Europe, Female, Follow-Up Studies, Humans, Incidence, Male, Middle Aged, Multivariate Analysis, Probability, Prognosis, Proportional Hazards Models, Randomized Controlled Trials as Topic, Remission Induction, Retrospective Studies, Transplantation, Homologous, Treatment Outcome, Young Adult, Dose Fractionation, Radiation, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute radiotherapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma radiotherapy, Whole-Body Irradiation adverse effects
- Abstract
Purpose: Total-body irradiation (TBI) is a major constituent of myeloablative conditioning regimens. The standard technique consists of 12 Gy in 6 fractions over a period of 3 days. The Standard-fractionation compAred to one-daily fRaction total body irrAdiation prior to tranSplant In LEUkemia patieNts (SARASIN) study aimed to compare standard fractionation with once-daily fractionation before transplant in leukemia., Methods and Materials: We retrospectively compared TBI regimens delivered in 2993 patients from the European Society for Blood and Marrow Transplantation database, who underwent transplantation between 2000 and 2014 for acute lymphoblastic leukemia (ALL, n = 1729) or acute myeloid leukemia (AML, n = 1264). TBI was delivered as either 12 Gy in 6 fractions (group 1, considered the reference group; 1362 ALL and 857 AML patients), 9 to 12 Gy in 2 fractions (group 2, 173 ALL and 256 AML patients), or 12 Gy in 3 to 4 fractions (group 3, 194 ALL and 151 AML patients)., Results: The median follow-up was 60 and 84 months in ALL and AML patients, respectively. At 5 years, the leukemia-free survival rate, overall survival rate, relapse incidence, and nonrelapse mortality rate were 46.6%, 50.4%, 28.8%, and 24.6%, respectively, in ALL patients and 46.6%, 48.9%, 29.7%, and 23.6%, respectively, in AML patients. In multivariate analyses, the outcomes of groups 2 and 3 were not statistically different from those in group 1. The cumulative incidence of secondary malignancies (SMs) was significantly higher in group 2 (7.2%; P < 10
-6 for group 2 vs group 1). However, group 2 was not associated with an increase in SMs when we considered non-T-cell-depleted transplant patients., Conclusions: We showed that the 12-Gy fractionated TBI dose delivered either in 2 fractions or in 1 fraction per day over a period of 3 to 4 days resulted in nonsignificant differences in disease control and survival. However, 1-day fractionation may be associated with a higher risk of mucositis and hemorrhagic cystitis. The absence of a significant difference in the SM incidence in the non-T-cell-depleted group should be interpreted with caution in the context of a retrospective study design. Our findings are important to consider for radiation therapy department organization. In-depth analyses of other nonlethal toxicities and late effects are required., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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37. 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
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38. 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
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39. 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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40. 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
- View/download PDF
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