290 results on '"Henk M. Lokhorst"'
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2. Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma
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Tineke Casneuf, Xu Steven Xu, Homer C. Adams, III, Amy E. Axel, Christopher Chiu, Imran Khan, Tahamtan Ahmadi, Xiaoyu Yan, Sagar Lonial, Torben Plesner, Henk M. Lokhorst, Niels W.C.J. van de Donk, Pamela L. Clemens, and A. Kate Sasser
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Daratumumab, a human CD38 imunoglobulin G 1κ monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on daratumumab efficacy and safety, were assessed. Daratumumab, like other CD38 antibodies, reduced NK-cell counts in peripheral blood mononuclear cells (PBMCs) of healthy donors in vitro. Data on NK-cell counts, clinical efficacy, and adverse events were pooled from two single-agent daratumumab studies, GEN501 and SIRIUS. In daratumumab-treated myeloma patients, total and activated NK-cell counts reduced rapidly in peripheral blood after the first dose, remained low over the course of treatment, and recovered after treatment ended. There was a clear maximum effect relationship between daratumumab dose and maximum reduction in NK cells. Similar reductions were observed in bone marrow. PBMCs from daratumumab-treated patients induced lysis by ADCC of CD38+ tumor cells in vitro, suggesting that the remaining NK cells retained cytotoxic functionality. There was no relationship between NK-cell count reduction and the efficacy or safety profile of daratumumab. Furthermore, although NK cell numbers are reduced after daratumumab treatment, they are not completely depleted and may still contribute to ADCC, clinical efficacy, and infection control.
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- 2017
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3. Immunotherapy in myeloma: how far have we come?
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Laurens E. Franssen, Tuna Mutis, Henk M. Lokhorst, and Niels W. C. J. van de Donk
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The treatment of multiple myeloma (MM) has evolved substantially over the past decades, leading to a significantly improved outcome of MM patients. The introduction of high-dose therapy, especially, and autologous stem cell transplantation, as well as the development of new drugs, such as immunomodulatory drugs (IMiDs) and proteasome inhibitors have contributed to the improvement in survival. However, eventually most MM patients relapse, which indicates that there is a need for new agents and novel treatment strategies. Importantly, the long-term survival in a subset of MM patients after allogeneic stem cell transplantation illustrates the potential of immunotherapy in MM, but allogeneic stem cell transplantation is also associated with a high rate of treatment-related mortality. Recently, a better insight into several immune-evasion mechanisms, which contribute to tumor progression, has resulted in the development of active and well-tolerated novel forms of immunotherapy. These immunotherapeutic agents can be used as monotherapy, or, even more successfully, in combination with other established anti-MM agents to further improve depth and duration of response by preventing the outgrowth of resistant clones. This review will discuss the mechanisms used by MM cells to evade the immune system, and also provide an overview of currently approved immunotherapeutic drugs, such as IMiDs (e.g. lenalidomide and pomalidomide) and monoclonal antibodies that target cell surface antigens present on the MM cell (e.g. elotuzumab and daratumumab), as well as novel immunotherapies (e.g. chimeric antigen receptor T-cells, bispecific antibodies and checkpoint inhibitors) currently in clinical development in MM.
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- 2019
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4. Sepantronium bromide (YM155) improves daratumumab-mediated cellular lysis of multiple myeloma cells by abrogation of bone marrow stromal cell-induced resistance
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Sanne J. de Haart, Lisa Holthof, Willy A. Noort, Monique C. Minnema, Maarten E. Emmelot, Tineke Aarts-Riemens, Parul Doshi, Kate Sasser, Huipin Yuan, Joost de Bruijn, Anton C.M. Martens, Niels W.C.J van de Donk, Henk M. Lokhorst, Richard W.J. Groen, and Tuna Mutis
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2016
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5. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma
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Esther Drent, Richard W.J. Groen, Willy A. Noort, Maria Themeli, Jeroen J. Lammerts van Bueren, Paul W.H.I. Parren, Jürgen Kuball, Zsolt Sebestyen, Huipin Yuan, Joost de Bruijn, Niels W.C.J. van de Donk, Anton C.M. Martens, Henk M. Lokhorst, and Tuna Mutis
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody sequences to generate second-generation retroviral CD38-chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite becoming CD38-negative during culture. CD38-chimeric antigen receptor-transduced T cells also displayed significant anti-tumor effects in a xenotransplant model, in which multiple myeloma tumors were grown in a human bone marrow-like microenvironment. CD38-chimeric antigen receptor-transduced T cells also appeared to lyse the CD38+ fractions of CD34+ hematopoietic progenitor cells, monocytes, natural killer cells, and to a lesser extent T and B cells but did not inhibit the outgrowth of progenitor cells into various myeloid lineages and, furthermore, were effectively controllable with a caspase-9-based suicide gene. These results signify the potential importance of CD38-chimeric antigen receptor-transduced T cells as therapeutic tools for CD38+ malignancies and warrant further efforts to diminish the undesired effects of this immunotherapy using appropriate strategies.
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- 2016
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6. Reduced relapse rate in upfront tandem autologous/reduced-intensity allogeneic transplantation in multiple myeloma only results in borderline non-significant prolongation of progression-free but not overall survival
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Henk M. Lokhorst, Bronno van der Holt, Jan J. Cornelissen, Marie José Kersten, Marinus van Oers, Reinier Raymakers, Monique C. Minnema, Sonja Zweegman, Gerard Bos, Nicolaas Schaap, Shulamiet Wittebol, Okke de Weerdt, Rianne Ammerlaan, and Pieter Sonneveld
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2015
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7. Extended follow up of high-dose melphalan and autologous stem cell transplantation after vincristine, doxorubicin, dexamethasone induction in amyloid light chain amyloidosis of the prospective phase II HOVON-41 study by the Dutch-Belgian Co-operative Trial Group for Hematology Oncology
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Bouke P.C. Hazenberg, Alexandra Croockewit, Bronno van der Holt, Sonja Zweegman, Gerard M.J. Bos, Michel Delforge, Reinier A.P. Raymakers, Pieter Sonneveld, Edo Vellenga, Pierre W. Wijermans, Peter A. von dem Borne, Marinus H. van Oers, Okke de Weerdt, Fokje M. Spoelstra, Henk M. Lokhorst, and for the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON)
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In a prospective multicenter phase II study, we evaluated the effect of three courses of vincristine, doxorubicin and dexamethasone followed by high-dose melphalan and autologous stem cell transplantation on an intention-to-treat basis. Sixty-nine newly diagnosed patients with amyloid light chain amyloidosis were included between November 2000 and January 2006: 37 men and 32 women with a median age of 56 years, including 46% of patients with cardiac and 22% of patients with involvement of 3 or 4 organs. Initial results presented in 2008 showed a 4-year overall survival rate of 62% among all the patients, while the 4-year survival rate after transplantation was 78%. Here we report the long-term follow-up data after a median follow up of 115 months of the patients still alive. Median survival of all patients was 96 months from registration and for the transplanted patients ten years from the date of transplantation. Twelve (12%) patients died during induction therapy with vincristine, doxorubicin and dexamethasone, including 8 patients (12%) due to treatment-related mortality. Two patients died within one month following high-dose melphalan. We conclude that vincristine, doxorubicin and dexamethasone should not be applied as induction therapy for intensification in amyloid light chain amyloidosis. However, a 2-step approach consisting of a non-intensive less toxic induction therapy followed by high-dose melphalan and autologous stem cell transplantation may result in extended survival in newly diagnosed patients with amyloid light chain amyloidosis (clinicaltrials.gov identifier: 01207094).
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- 2015
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8. Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide
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Inger S. Nijhof, Jeroen J. Lammerts van Bueren, Berris van Kessel, Pascale Andre, Yannis Morel, Henk M. Lokhorst, Niels W.C.J. van de Donk, Paul W.H.I. Parren, and Tuna Mutis
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Despite recent treatment improvements, multiple myeloma remains an incurable disease. Since antibody-dependent cell-mediated cytotoxicity is an important effector mechanism of daratumumab, we explored the possibility of improving daratumumab-mediated cell-mediated cytotoxicity by blocking natural killer cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of natural killer cells with the immune modulatory drug lenalidomide. In 4-hour antibody-dependent cell-mediated cytotoxicity assays, IPH2102 did not induce lysis of multiple myeloma cell lines, but it did significantly augment daratumumab-induced myeloma cell lysis. Also in an ex vivo setting, IPH2102 synergistically improved daratumumab-dependent lysis of primary myeloma cells in bone marrow mononuclear cells (n=21), especially in patients carrying the FcγRIIIa-158F allele or the FcγRIIa-131R allele, who bind IgG1 with lower affinity than patients carrying the FcγRIIIa-158V allele or the FcγRIIa-131H allele. Finally, a further synergistically improved myeloma cell lysis with the daratumumab-IPH2102 combination was observed by adding lenalidomide, which suggests that more effective treatment strategies can be designed for multiple myeloma by combining daratumumab with agents that independently modulate natural killer cell function.
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- 2015
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9. Identification of minor histocompatibility antigens based on the 1000 Genomes Project
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Rimke Oostvogels, Henk M. Lokhorst, Monique C. Minnema, Maureen van Elk, Kelly van den Oudenalder, Eric Spierings, Tuna Mutis, and Robbert M. Spaapen
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Minor histocompatibility antigens are highly immunogeneic polymorphic peptides playing crucial roles in the clinical outcome of HLA-identical allogeneic stem cell transplantation. Although the introduction of genome-wide association-based strategies significantly has accelerated the identification of minor histocompatibility antigens over the past years, more efficient, rapid and robust identification techniques are required for a better understanding of the immunobiology of minor histocompatibility antigens and for their optimal clinical application in the treatment of hematologic malignancies. To develop a strategy that can overcome the drawbacks of all earlier strategies, we now integrated our previously developed genetic correlation analysis methodology with the comprehensive genomic databases from the 1000 Genomes Project. We show that the data set of the 1000 Genomes Project is suitable to identify all of the previously known minor histocompatibility antigens. Moreover, we demonstrate the power of this novel approach by the identification of the new HLA-DP4 restricted minor histocompatibility antigen UTDP4-1, which despite extensive efforts could not be identified using any of the previously developed biochemical, molecular biological or genetic strategies. The 1000 Genomes Project-based identification of minor histocompatibility antigens thus represents a very convenient and robust method for the identification of new targets for cancer therapy after allogeneic stem cell transplantation.
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- 2014
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10. Secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation in multiple myeloma
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Marian F. Schmitz, Henny G. Otten, Laurens E. Franssen, Suzanne van Dorp, Theo Strooisma, Henk M. Lokhorst, and Niels W.C.J. van de Donk
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In the course of multiple myeloma, patients may develop a M-protein band different from the original: secondary monoclonal gammopathy of undetermined significance. In this retrospective single center analysis, we describe the occurrence and clinical relevance of secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation (post-transplant monoclonal gammopathy of undetermined significance). A total of 138 patients who had undergone 139 allogeneic stem cell transplantations (39.6% in the upfront setting and 60.4% for relapsed multiple myeloma) were included in the study. Sixty-seven (48.2%) patients developed secondary monoclonal gammopathy of undetermined significance, after a median latency of 6.9 months. Secondary monoclonal gammopathy of undetermined significance occurred more often in patients who achieved at least very good partial response after allogeneic stem cell transplantation, compared to partial response or less (54.8% vs. 26.5%; P=0.005). The incidence was also higher in the upfront setting as compared to relapsed disease, or with a sibling donor compared to matched unrelated donor, but less often after T-cell depletion. Importantly, development of post-transplant monoclonal gammopathy of undetermined significance as a time-dependent variable independently predicted for superior progression-free and overall survival (median progression-free survival 37.5 vs. 6.3 months, P
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- 2014
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11. The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network
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Niels W.C.J. van de Donk, Antonio Palumbo, Hans Erik Johnsen, Monika Engelhardt, Francesca Gay, Henrik Gregersen, Roman Hajek, Martina Kleber, Heinz Ludwig, Gareth Morgan, Pellegrino Musto, Torben Plesner, Orhan Sezer, Evangelos Terpos, Anders Waage, Sonja Zweegman, Hermann Einsele, Pieter Sonneveld, and Henk M. Lokhorst
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Monoclonal gammopathy of undetermined significance is one of the most common pre-malignant disorders. IgG and IgA monoclonal gammopathy of undetermined significance are precursor conditions of multiple myeloma; light-chain monoclonal gammopathy of undetermined significance of light-chain multiple myeloma; and IgM monoclonal gammopathy of undetermined significance of Waldenström’s macroglobulinemia and other lymphoproliferative disorders. Clonal burden, as determined by bone marrow plasma cell percentage or M-protein level, as well as biological characteristics, including heavy chain isotype and light chain production, are helpful in predicting risk of progression of monoclonal gammopathy of undetermined significance to symptomatic disease. Furthermore, alterations in the bone marrow microenvironment of monoclonal gammopathy of undetermined significance patients result in an increased risk of venous and arterial thrombosis, infections, osteoporosis, and bone fractures. In addition, the small clone may occasionally be responsible for severe organ damage through the production of a monoclonal protein that has autoantibody activity or deposits in tissues. These disorders are rare and often require therapy directed at eradication of the underlying plasma cell or lymphoplasmacytic clone. In this review, we provide an overview of the clinical relevance of monoclonal gammopathy of undetermined significance. We also give general recommendations of how to diagnose and manage patients with monoclonal gammopathy of undetermined significance.
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- 2014
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12. Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial
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Christof Scheid, Pieter Sonneveld, Ingo G.H. Schmidt-Wolf, Bronno van der Holt, Laila el Jarari, Uta Bertsch, Hans Salwender, Sonja Zweegman, Igor Wolfgang Blau, Edo Vellenga, Katja Weisel, Michael Pfreundschuh, Kon-Siong Jie, Kai Neben, Helgi van de Velde, Ulrich Duehrsen, M. Ron Schaafsma, Walter Lindemann, Marie José Kersten, Norma Peter, Mathias Hänel, Sandra Croockewit, Hans Martin, Shulamiet Wittebol, Gerard MJ Bos, Marinus van Marwijk-Kooy, Pierre Wijermans, Hartmut Goldschmidt, and Henk M. Lokhorst
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Renal impairment is frequent in patients with multiple myeloma and is correlated with an inferior prognosis. This analysis evaluates the prognostic role of renal impairment in patients with myeloma treated with bortezomib before and after autologous stem cell transplantation within a prospective randomized phase III trial. Eight hundred and twenty-seven newly diagnosed myeloma patients in the HOVON-65/GMMG-HD4 trial were randomized to receive three cycles of vincristine, adriamycin, dexamethasone (VAD) or bortezomib, adriamycin, dexamethasone (PAD) followed by autologous stem cell transplantation and maintenance with thalidomide 50 mg daily (VAD-arm) or bortezomib 1.3 mg/m2 every 2 weeks (PAD-arm). Baseline serum creatinine was less than 2 mg/dL (Durie-Salmon-stage A) in 746 patients and 2 mg/dL or higher (stage B) in 81. In myeloma patients with a baseline creatinine ≥2 mg/dL the renal response rate was 63% in the VAD-arm and 81% in the PAD-arm (P=0.31). The overall myeloma response rate was 64% in the VAD-arm versus 89% in the PAD-arm with 13% complete responses in the VAD-arm versus 36% in the PAD-arm (P=0.01). Overall survival at 3 years for patients with a baseline creatinine ≥2 mg/dL was 34% in the VAD-arm versus 74% in the PAD-arm (P
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- 2014
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13. Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab
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Michael. S. van der Veer, Michel de Weers, Berris van Kessel, Joost M. Bakker, Shulamiet Wittebol, Paul W.H.I. Parren, Henk M. Lokhorst, and Tuna Mutis
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis.Design and Methods To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment.Results Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab-induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cell-mediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment.Conclusions Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma.
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- 2011
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14. A bioluminescence imaging based in vivo model for preclinical testing of novel cellular immunotherapy strategies to improve the graft-versus-myeloma effect
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Henk Rozemuller, Ellen van der Spek, Lijnie H. Bogers-Boer, Mieke C. Zwart, Vivienne Verweij, Maarten Emmelot, Richard W. Groen, Robbert Spaapen, Andries C. Bloem, Henk M. Lokhorst, Tuna Mutis, and Anton C. Martens
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background The development and preclinical testing of novel immunotherapy strategies for multiple myeloma can benefit substantially from a humanized animal model that enables quantitative real-time monitoring of tumor progression. Here we have explored the feasibility of establishing such a model in immunodeficient RAG2−/−γc−/− mice, by utilizing non-invasive bioluminescent imaging for real-time monitoring of multiple myeloma cell growth.Design and Methods Seven multiple myeloma cell lines, marked with a green fluorescent protein firefly luciferase fusion gene, were intravenously injected into RAG2−/−γc−/− mice. Tumor localization and outgrowth was monitored by bioluminescent imaging. The sensitivity of this imaging technique was compared to that of free immumoglobulin light chain -based myeloma monitoring. Established tumors were treated with radiotherapy or with allogeneic peripheral blood mononuclear cell infusions to evaluate the application areas of the model.Results Five out of seven tested multiple myeloma cell lines progressed as myeloma-like tumors predominantly in the bone marrow; the two other lines showed additional growth in soft tissues. In our model bioluminescent imaging appeared superior to free light chain-based monitoring and also allowed semi-quantitative monitoring of individual foci of multiple myeloma. Tumors treated with radiotherapy showed temporary regression. However, infusion of allogeneic peripheral blood mononuclear cells resulted in the development of xenogeneic graft-versus-host-disease and a powerful cell dose-dependent graft-versus-myeloma effect, resulting in complete eradication of tumors, depending on the in vitro immunogenicity of the inoculated multiple myeloma cells.Conclusions Our results indicate that this new model allows convenient and sensitive real-time monitoring of cellular approaches for immunotherapy of multiple myeloma-like tumors with different immunogenicities. This model, therefore, allows comprehensive preclinical evaluation of novel combination therapies for multiple myeloma.
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- 2008
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15. Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma
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Henk M. Lokhorst, Ingo Schmidt-Wolf, Pieter Sonneveld, Bronno van der Holt, Hans Martin, Rene Barge, Uta Bertsch, Jana Schlenzka, Gerard M.J. Bos, Sandra Croockewit, Sonja Zweegman, Iris Breitkreutz, Peter Joosten, Christof Scheid, Marinus van Marwijk-Kooy, Hans-Juergen Salwender, Marinus H.J. van Oers, Ron Schaafsma, Ralph Naumann, Harm Sinnige, Igor Blau, Michel Delforge, Okke de Weerdt, Pierre Wijermans, Shulamiet Wittebol, Ulrich Duersen, Edo Vellenga, and Hartmut Goldschmidt
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In the prospective phase 3 HOVON-50/GMMG-HD3 trial, patients randomized to TAD (thalidomide, doxorubicin, dexamethasone) had a significantly higher response rate (at least PR) after induction compared with patients randomized to VAD (vincristine, adriamycin, dexamethasone, 72% vs. 54%, p
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- 2008
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16. Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term follow-up of the Dutch Cooperative Group HOVON 24 trial
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Pieter Sonneveld, Bronno van der Holt, Christine M. Segeren, Edo Vellenga, Alexandra J. Croockewit, Gregor E.G. Verhoef, Jan J. Cornelissen, Martijn R. Schaafsma, Marinus H.J. van Oers, Pierre W. Wijermans, Petra H.M. Westveer, and Henk M. Lokhorst
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background and Objectives The Dutch-Belgian HOVON group performed a randomized phase 3 trial to compare single non-myeloablative intensive treatment with double, intensive treatment in previously untreated patients with multiple myeloma (MM).Design and Methods Three hundred and three patients with stage II/III MM were randomized after VAD induction chemotherapy to receive two cycles of non-myeloablative intermediate-dose melphalan (70 mg/m2) (single treatment) or the same regimen followed by cyclophosphamide 120 mg/kg iv plus total body irradiation (TBI) 9 Gy and autologous stem cell transplantation (double, intensive treatment). In both treatment arms interferon αIIa was given as maintenance until relapse/progression.Results A significantly higher proportion of patients achieved a complete remission (CR) on protocol treatment with double, intensive therapy (32% vs 13%, p
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- 2007
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17. Supplementary Figure 2 from T Cells Specific for an Unconventional Natural Antigen Fail to Recognize Leukemic Cells
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Robbert M. Spaapen, Marieke Griffioen, Tuna Mutis, J.H. Frederik Falkenburg, Henk M. Lokhorst, Marlieke L.M. Jongsma, Sophie Bliss, Maria W. Honders, Edith D. van der Meijden, Cornelis A.M. van Bergen, Rimke Oostvogels, and Margot J. Pont
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Supplementary Figure 2. The generation of the LB-TTK-1D peptide is proteasome-dependent. LB-TTK-1D antigen positive EBV-LCLs were treated with increasing concentrations of the proteasome inhibitor bortezomib for 48h, washed and exposed to LB-TTK-1D-specific T cells (clone 10-5). T cell-produced IFN-γ was determined in the supernatant of the cultures by ELISA. Depicted are OD450 values.
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- 2023
18. Data from T Cells Specific for an Unconventional Natural Antigen Fail to Recognize Leukemic Cells
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Robbert M. Spaapen, Marieke Griffioen, Tuna Mutis, J.H. Frederik Falkenburg, Henk M. Lokhorst, Marlieke L.M. Jongsma, Sophie Bliss, Maria W. Honders, Edith D. van der Meijden, Cornelis A.M. van Bergen, Rimke Oostvogels, and Margot J. Pont
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MHC-bound peptides from aberrant proteins may be a specific immunotherapeutic target on cancer cells. Because of difficulties in identifying such antigens, viral or model antigens have so far been used to study their biological relevance. We here identify a naturally existing human T-cell epitope derived from a truncated protein. The antigenic peptide is derived from the gene TTK only through an alternative transcript containing a premature termination codon that may target the transcript for nonsense-mediated decay (NMD). This antigen is recognized by HLA-A*02:01–restricted CD8+ T cells derived from an allotransplanted leukemia patient. Functional analyses showed that these T cells failed to recognize several HLA-matched primary leukemic cells that expressed the alternative TTK transcript. Conventional antigen processing and presentation were not affected, suggesting that leukemic cells modify the generation of antigens processed from aberrant proteins. This natural TTK epitope provides insights in the source of transcripts producing antigenic epitopes in healthy and leukemic cells. Our data underscore potential pitfalls of targeting NMD-derived or other unconventionally generated epitopes as immunotherapeutic approach.
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- 2023
19. Supplementary Figure 1 from T Cells Specific for an Unconventional Natural Antigen Fail to Recognize Leukemic Cells
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Robbert M. Spaapen, Marieke Griffioen, Tuna Mutis, J.H. Frederik Falkenburg, Henk M. Lokhorst, Marlieke L.M. Jongsma, Sophie Bliss, Maria W. Honders, Edith D. van der Meijden, Cornelis A.M. van Bergen, Rimke Oostvogels, and Margot J. Pont
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Supplementary Figure 1. The LB-TTK-1D-specific (clone 10-5) and USP11-specific T cell clones have a similar affinity for their cognate peptide. Synthetic peptides RLHDGRVFV (peptideTTK) or FTWEGLYNV (peptideUSP11) were loaded on T2 cells in a serial dilution. The depicted T cell clones were stimulated using these target cells followed by determination of IFN-γ secretion in the supernatant (ELISA). Calculated EC50 values are depicted.
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- 2023
20. Supplementary Figure 2 from Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance
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Tuna Mutis, Constantine S. Mitsiades, Anton C. Martens, Henk M. Lokhorst, Jana Jakubikova, Douglas W. McMillin, Richard W.J. Groen, Huipin Yuan, Niels Bovenschen, Tineke Aarts-Riemens, Julie H. Huang, Monique C. Minnema, Niels W.C.J. van de Donk, and Sanne J. de Haart
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Supplementary Figure 2 - PDF file 50K, Accessory cells protect MM cells from WT-1 specific CTLs. U266 cells were co-cultured with WT-1 specific T cells in presence and absence of different accessory cells. MM cell viability was determined 24h after addition of T cells by CS-BLI (A). Granzyme B production in the supernatant was determined by ELISA (B). Significance of inhibition of MM cell survival in the presence of accessory cells was tested by unpaired two tailed student's t test. *= p
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- 2023
21. Supplemental Data from Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab
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Niels W.C.J. van de Donk, Tuna Mutis, A. Kate Sasser, Henk M. Lokhorst, Torben Plesner, Christopher Chiu, Richard W.J. Groen, Pino J. Poddighe, René J.P. Musters, Johan van Meerloo, Sonja Zweegman, Marloes E.C. Broekmans, Andries C. Bloem, Jeroen F. van Velzen, Berris van Kessel, Inger S. Nijhof, Kris A. Frerichs, and Jakub Krejcik
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Supplemental Methods, Supplementary Tables, Supplementary Figure Legends
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- 2023
22. Supplementary Figure 1 from Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance
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Tuna Mutis, Constantine S. Mitsiades, Anton C. Martens, Henk M. Lokhorst, Jana Jakubikova, Douglas W. McMillin, Richard W.J. Groen, Huipin Yuan, Niels Bovenschen, Tineke Aarts-Riemens, Julie H. Huang, Monique C. Minnema, Niels W.C.J. van de Donk, and Sanne J. de Haart
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Supplementary Figure 1 - PDF file 53K, Antigen specific, HLA-restricted and dose-dependent recognition of the MM cell lines U266 and UM9, but not of accessory cells by CD8+ and CD4+ mHag-specific CTLs. The CD4+ (A) and CD8+ (B) CTLs were co-cultured with the luc+ MM cell lines UM9 and U266 in different effector to target ratios. The HLA- and mHag typing of these MM cell lines are indicated. MM cell survival was determined 24 h after addition of T cells by CS-BLI. Results represent the mean values of triplicate cultures (+/- SEM). Results are representative of 3 independent assays. In (C and D) CD4+ (C) and CD8+ (D) CTLs were co-cultured with accessory cells. Accessory cell survival was determined 24h after addition of T cells by FACS annexine V/ propidium iodide staining of CD4 and CD8 negative cells in the co-cultures. Results are depicted as % surviving cells, measured as relative number annexin V/propidium iodide negative cells, compared to no T cells control
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- 2023
23. Supplementary Figure Legend from Human Regulatory T Cells Do Not Suppress the Antitumor Immunity in the Bone Marrow: A Role for Bone Marrow Stromal Cells in Neutralizing Regulatory T Cells
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Tuna Mutis, Anton C. Martens, Henk M. Lokhorst, Gert Storm, Richard W.J. Groen, Bianka Martini, Henk Rozemuller, Maarten E. Emmelot, and Teun Guichelaar
- Abstract
PDF file - 53K
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- 2023
24. Supplementary Figure 3 from Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance
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Tuna Mutis, Constantine S. Mitsiades, Anton C. Martens, Henk M. Lokhorst, Jana Jakubikova, Douglas W. McMillin, Richard W.J. Groen, Huipin Yuan, Niels Bovenschen, Tineke Aarts-Riemens, Julie H. Huang, Monique C. Minnema, Niels W.C.J. van de Donk, and Sanne J. de Haart
- Abstract
Supplementary Figure 3 - PDF file 55K, RGDw reduces adhesion of MM cells to accessory cells. Adherent HS-5 en HUVEC accessory cells were incubated with RGDw or an irrelevant peptide for 1hour. After washing away the unbound peptide, UM9 (A) or U266 (B) cells were added and incubated overnight. Plates were reversely centrifuged to determine adhesion to accessory cells. Results represent the mean values of triplicate cultures (+/- SEM). Differences in adhesion were tested by unpaired two tailed student's t test. *= p
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- 2023
25. Supplementary Figure 3 from Human Regulatory T Cells Do Not Suppress the Antitumor Immunity in the Bone Marrow: A Role for Bone Marrow Stromal Cells in Neutralizing Regulatory T Cells
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Tuna Mutis, Anton C. Martens, Henk M. Lokhorst, Gert Storm, Richard W.J. Groen, Bianka Martini, Henk Rozemuller, Maarten E. Emmelot, and Teun Guichelaar
- Abstract
PDF file - 111K, GVHD and GvT regulation in the LME-1 MM tumor model. (A) GvHD scores at weeks 3, 4,and 5. The total score is the sum of the scores for weight loss ( 0=0-10 %; 1=10-20%; 2=>20%. ) , mobility (0= mobile; 1= diminished mobility;2 = immobile) and fur appearance (0=normal; 1= ruffled fur; 2= ruffled fur + red swollen skin; 3= ruffled fur + red swollen skin + patchy alopecia) (B) CD4 and CD8 T cell counts in peripheral blood, BM and spleen at week 3. (C) BLI imaging results of three representative animals per group at week 3. The depicted areas indicate the regions of extramedullar vs medullar tumors . The BLI counts in the corresponding table are in thousands. For each mouse total, extramedullary, and medullary ( total-extramedullary) tumor load are indicated separately. The mean values of the ratio of extramedullary vs medullary tumor load are also depicted.
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- 2023
26. Supplementary Data from Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor–engineered T Cells
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Maria Themeli, Tuna Mutis, Richard W.J. Groen, Henk M. Lokhorst, Michel Sadelain, Joost de Bruijn, Huipin Yuan, Sonja Zweegman, Niels W.C.J. van de Donk, Ruud Ruiter, Renée Poels, and Esther Drent
- Abstract
Supplementary methods and data
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- 2023
27. Supplementary Figure 5 from Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance
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Tuna Mutis, Constantine S. Mitsiades, Anton C. Martens, Henk M. Lokhorst, Jana Jakubikova, Douglas W. McMillin, Richard W.J. Groen, Huipin Yuan, Niels Bovenschen, Tineke Aarts-Riemens, Julie H. Huang, Monique C. Minnema, Niels W.C.J. van de Donk, and Sanne J. de Haart
- Abstract
Supplementary Figure 5 - PDF file 41K, Bortezomib does not improve the CTL mediated lysis of Fas negative L363 cellsL3L3 reactive CD8+CTLs were incubated at the indicated effector to target ratios with luc-transduced L3L3 cells alone or in the presence of various dilutions of bortezomib. The CTL mediated and bortezomib mediated lysis of L3L3 cells was determined after 48 hours by BLI. Results are depicted as % surviving cells using the triplicate cultures without T cells and bortezomib as the 100% survival control
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- 2023
28. Data from Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance
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Tuna Mutis, Constantine S. Mitsiades, Anton C. Martens, Henk M. Lokhorst, Jana Jakubikova, Douglas W. McMillin, Richard W.J. Groen, Huipin Yuan, Niels Bovenschen, Tineke Aarts-Riemens, Julie H. Huang, Monique C. Minnema, Niels W.C.J. van de Donk, and Sanne J. de Haart
- Abstract
Purpose: Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells.Experimental Design: Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4+ or CD8+ CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants.Results: Bone marrow stromal cells from patients with multiple myeloma and healthy individuals, as well as vascular endothelial cells, significantly inhibited the lysis of multiple myeloma cells in a cell–cell contact-dependent manner and without substantial T-cell suppression, thus showing the induction of a cell adhesion-mediated immune resistance (CAM-IR) against CTL lysis. Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Reconstitution of Fas expression with bortezomib enhanced the CTL-mediated lysis of multiple myeloma cells. Repressing survivin with the small-molecule YM155 synergized with CTLs and abrogated CAM-IR in vitro and in vivo.Conclusion: These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR. Clin Cancer Res; 19(20); 5591–601. ©2013 AACR.
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- 2023
29. Supplementary Figure Legends from Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance
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Tuna Mutis, Constantine S. Mitsiades, Anton C. Martens, Henk M. Lokhorst, Jana Jakubikova, Douglas W. McMillin, Richard W.J. Groen, Huipin Yuan, Niels Bovenschen, Tineke Aarts-Riemens, Julie H. Huang, Monique C. Minnema, Niels W.C.J. van de Donk, and Sanne J. de Haart
- Abstract
Supplementary Figure Legends - PDF file 73K, Legends for supplementary figures
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- 2023
30. Supplementary Figure 1 from Human Regulatory T Cells Do Not Suppress the Antitumor Immunity in the Bone Marrow: A Role for Bone Marrow Stromal Cells in Neutralizing Regulatory T Cells
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Tuna Mutis, Anton C. Martens, Henk M. Lokhorst, Gert Storm, Richard W.J. Groen, Bianka Martini, Henk Rozemuller, Maarten E. Emmelot, and Teun Guichelaar
- Abstract
PDF file - 49K, Ex vivo expansion and suppressor capacity of Tregs. (A) Ex vivo expansion rate of CD4+CD25+ Tregs isolated from peripheral blood. (B) Suppressive activity of ex vivo cultured Tregs on CD4+CD25- effector T cells stimulated with CD3/CD28 expander beads. Ex vivo cultures and suppression assays were executed as indicated in the material and methods section. Presented data are representative of >5 individual Treg cultures from different donors. Error bars indicate the SEM of at least duplicate measurements. The expanded Treg cultures contained 70% +/- 3% Foxp3+ T cells which were also negative for CD127. The cultures also contained 4.5+/-3.6 % IL-17 producing cells as detected after stimulation with PMA/Ionomycin (see also ref 20)
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- 2023
31. Supplementary Figure 6 from Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance
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Tuna Mutis, Constantine S. Mitsiades, Anton C. Martens, Henk M. Lokhorst, Jana Jakubikova, Douglas W. McMillin, Richard W.J. Groen, Huipin Yuan, Niels Bovenschen, Tineke Aarts-Riemens, Julie H. Huang, Monique C. Minnema, Niels W.C.J. van de Donk, and Sanne J. de Haart
- Abstract
Supplementary Figure 6 - PDF file 74K, Synergistic interaction of YM155 and CTLs. In A, the effect of YM155 on survivin and MCL-1 protein levels of MM cells is shown. The cells were cultured with YM155 during 24h and the western blot assays were carried out as indicated in material methods. Band intensities were quantified using image J software, calculated as relative values to the control protein tubuline and plotted as relative to the expression levels of cells cultured without YM155. In B, the type of interaction between YM155 and CTLs (see figure 5C-D) in the presence of accessory cells was analyzed using Compusyn software (version 1.0, 2004 �). In the plots (A) the CI values corresponding to the doses in figure 5 are shown. A CI value of 1 indicates synergy, additive effects or antagonism, respectively. In C the supernatants of assays as described in Fig 5C-D granzyme B release was measured using ELISA (B). Results are expressed as the mean values of the triplicate cultures. Error bars represent the SEM. Results are representative of 3 independent assays
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- 2023
32. Supplementary Figure 5 from Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab
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Niels W.C.J. van de Donk, Tuna Mutis, A. Kate Sasser, Henk M. Lokhorst, Torben Plesner, Christopher Chiu, Richard W.J. Groen, Pino J. Poddighe, René J.P. Musters, Johan van Meerloo, Sonja Zweegman, Marloes E.C. Broekmans, Andries C. Bloem, Jeroen F. van Velzen, Berris van Kessel, Inger S. Nijhof, Kris A. Frerichs, and Jakub Krejcik
- Abstract
Monocytes take up AF488-labeled daratumumab-CD38 complexes from PKH-26-stained UM9 cells.
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- 2023
33. Supplementary Figure 2 from Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab
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Niels W.C.J. van de Donk, Tuna Mutis, A. Kate Sasser, Henk M. Lokhorst, Torben Plesner, Christopher Chiu, Richard W.J. Groen, Pino J. Poddighe, René J.P. Musters, Johan van Meerloo, Sonja Zweegman, Marloes E.C. Broekmans, Andries C. Bloem, Jeroen F. van Velzen, Berris van Kessel, Inger S. Nijhof, Kris A. Frerichs, and Jakub Krejcik
- Abstract
Daratumumab-mediated CD38 reduction of MM cells in the presence of PBMCs as shown by Western blot analysis.
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- 2023
34. Data from Human Regulatory T Cells Do Not Suppress the Antitumor Immunity in the Bone Marrow: A Role for Bone Marrow Stromal Cells in Neutralizing Regulatory T Cells
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Tuna Mutis, Anton C. Martens, Henk M. Lokhorst, Gert Storm, Richard W.J. Groen, Bianka Martini, Henk Rozemuller, Maarten E. Emmelot, and Teun Guichelaar
- Abstract
Purpose: Regulatory T cells (Tregs) are potent tools to prevent graft-versus-host disease (GVHD) induced after allogeneic stem cell transplantation or donor lymphocyte infusions. Toward clinical application of Tregs for GVHD treatment, we investigated the impact of Tregs on the therapeutic graft-versus-tumor (GVT) effect against human multiple myeloma tumors with various immunogenicities, progression rates, and localizations in a humanized murine model.Experimental Design: Immunodeficient Rag2−/−γc−/− mice, bearing various human multiple myeloma tumors, were treated with human peripheral blood mononuclear cell (PBMC) alone or together with autologous ex vivo cultured Tregs. Mice were analyzed for the in vivo engraftment, homing of T-cell subsets, development of GVHD and GVT. In additional in vitro assays, Tregs that were cultured together with bone marrow stromal cells were analyzed for phenotype and functions.Results: Treatment with PBMC alone induced variable degrees of antitumor response, depending on the immunogenicity and the growth rate of the tumor. Coinfusion of Tregs did not impair the antitumor response against tumors residing within the bone marrow, irrespective of their immunogenicity or growth rates. In contrast, Tregs readily inhibited the antitumor effect against tumors growing outside the bone marrow. Exploring this remarkable phenomenon, we discovered that bone marrow stroma neutralizes the suppressive activity of Tregs in part via production of interleukin (IL)-1β/IL-6. We furthermore found in vitro and in vivo evidence of conversion of Tregs into IL-17–producing T cells in the bone marrow environment.Conclusions: These results provide new insights into the Treg immunobiology and indicate the conditional benefits of future Treg-based therapies. Clin Cancer Res; 19(6); 1467–75. ©2012 AACR.
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- 2023
35. Data from Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor–engineered T Cells
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Maria Themeli, Tuna Mutis, Richard W.J. Groen, Henk M. Lokhorst, Michel Sadelain, Joost de Bruijn, Huipin Yuan, Sonja Zweegman, Niels W.C.J. van de Donk, Ruud Ruiter, Renée Poels, and Esther Drent
- Abstract
Purpose:Targeting nonspecific, tumor-associated antigens (TAA) with chimeric antigen receptors (CAR) requires specific attention to restrict possible detrimental on-target/off-tumor effects. A reduced affinity may direct CAR-engineered T (CAR-T) cells to tumor cells expressing high TAA levels while sparing low expressing normal tissues. However, decreasing the affinity of the CAR-target binding may compromise the overall antitumor effects. Here, we demonstrate the prime importance of the type of intracellular signaling on the function of low-affinity CAR-T cells.Experimental Design:We used a series of single-chain variable fragments (scFv) with five different affinities targeting the same epitope of the multiple myeloma–associated CD38 antigen. The scFvs were incorporated in three different CAR costimulation designs and we evaluated the antitumor functionality and off-tumor toxicity of the generated CAR-T cells in vitro and in vivo.Results:We show that the inferior cytotoxicity and cytokine secretion mediated by CD38 CARs of very low–affinity (Kd < 1.9 × 10−6 mol/L) bearing a 4-1BB intracellular domain can be significantly improved when a CD28 costimulatory domain is used. Additional 4-1BB signaling mediated by the coexpression of 4-1BBL provided the CD28-based CD38 CAR-T cells with superior proliferative capacity, preservation of a central memory phenotype, and significantly improved in vivo antitumor function, while preserving their ability to discriminate target antigen density.Conclusions:A combinatorial costimulatory design allows the use of very low–affinity binding domains (Kd < 1 μmol/L) for the construction of safe but also optimally effective CAR-T cells. Thus, very-low-affinity scFvs empowered by selected costimulatory elements can enhance the clinical potential of TAA-targeting CARs.
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- 2023
36. Supplementary Figure 4 from Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance
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Tuna Mutis, Constantine S. Mitsiades, Anton C. Martens, Henk M. Lokhorst, Jana Jakubikova, Douglas W. McMillin, Richard W.J. Groen, Huipin Yuan, Niels Bovenschen, Tineke Aarts-Riemens, Julie H. Huang, Monique C. Minnema, Niels W.C.J. van de Donk, and Sanne J. de Haart
- Abstract
Supplementary Figure 4 - PDF file 219K, FasL upregulation on CTLs upon MM cell recognition is not hampered by presence of accessory cells. CD4+ (A) and CD8+ (B) CTLs were cultured alone (unstimulated) or in the presence of tumor cells and in presence or absence of accessory cells as indicated. After 3 hours of co-incubation CTLs were evaluated for CD178 (Fas ligand) expression. Percentage of FasL expressing cells is indicated
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- 2023
37. Supplementary Figure 1 from Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab
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Niels W.C.J. van de Donk, Tuna Mutis, A. Kate Sasser, Henk M. Lokhorst, Torben Plesner, Christopher Chiu, Richard W.J. Groen, Pino J. Poddighe, René J.P. Musters, Johan van Meerloo, Sonja Zweegman, Marloes E.C. Broekmans, Andries C. Bloem, Jeroen F. van Velzen, Berris van Kessel, Inger S. Nijhof, Kris A. Frerichs, and Jakub Krejcik
- Abstract
Loss of CD38 from the MM cell membrane is associated with reduced CDC and ADCC
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- 2023
38. Supplementary Figure 2 from Human Regulatory T Cells Do Not Suppress the Antitumor Immunity in the Bone Marrow: A Role for Bone Marrow Stromal Cells in Neutralizing Regulatory T Cells
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Tuna Mutis, Anton C. Martens, Henk M. Lokhorst, Gert Storm, Richard W.J. Groen, Bianka Martini, Henk Rozemuller, Maarten E. Emmelot, and Teun Guichelaar
- Abstract
PDF file - 54K, Human Tregs allow GvT against murine lymphoma tumors. Human PBMC were infused alone or together with expanded human Tregs to treat immune deficient mice carrying murine Luciferase+ A20 lymphoma cells in the bone marrow. PBMC (n=10), PBMC + Treg (n=9), untreated control group (n=10) (A) Kaplan Meier survival curves of mice, which all were sacrificed due to paralysis ***, p
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- 2023
39. Data from Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab
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Niels W.C.J. van de Donk, Tuna Mutis, A. Kate Sasser, Henk M. Lokhorst, Torben Plesner, Christopher Chiu, Richard W.J. Groen, Pino J. Poddighe, René J.P. Musters, Johan van Meerloo, Sonja Zweegman, Marloes E.C. Broekmans, Andries C. Bloem, Jeroen F. van Velzen, Berris van Kessel, Inger S. Nijhof, Kris A. Frerichs, and Jakub Krejcik
- Abstract
Purpose: Daratumumab treatment results in a marked reduction of CD38 expression on multiple myeloma cells. The aim of this study was to investigate the clinical implications and the underlying mechanisms of daratumumab-mediated CD38 reduction.Experimental Design: We evaluated the effect of daratumumab alone or in combination with lenalidomide-dexamethasone, on CD38 levels of multiple myeloma cells and nontumor immune cells in the GEN501 study (daratumumab monotherapy) and the GEN503 study (daratumumab combined with lenalidomide-dexamethasone). In vitro assays were also performed.Results: In both trials, daratumumab reduced CD38 expression on multiple myeloma cells within hours after starting the first infusion, regardless of depth and duration of the response. In addition, CD38 expression on nontumor immune cells, including natural killer cells, T cells, B cells, and monocytes, was also reduced irrespective of alterations in their absolute numbers during therapy. In-depth analyses revealed that CD38 levels of multiple myeloma cells were only reduced in the presence of complement or effector cells, suggesting that the rapid elimination of CD38high multiple myeloma cells can contribute to CD38 reduction. In addition, we discovered that daratumumab–CD38 complexes and accompanying cell membrane were actively transferred from multiple myeloma cells to monocytes and granulocytes. This process of trogocytosis was also associated with reduced surface levels of some other membrane proteins, including CD49d, CD56, and CD138.Conclusions: Daratumumab rapidly reduced CD38 expression levels, at least in part, through trogocytosis. Importantly, all these effects also occurred in patients with deep and durable responses, thus excluding CD38 reduction alone as a mechanism of daratumumab resistance.The trials were registered at www.clinicaltrials.gov as NCT00574288 (GEN501) and NCT1615029 (GEN503). Clin Cancer Res; 23(24); 7498–511. ©2017 AACR.
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- 2023
40. Supplementary Figure 3 from Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab
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Niels W.C.J. van de Donk, Tuna Mutis, A. Kate Sasser, Henk M. Lokhorst, Torben Plesner, Christopher Chiu, Richard W.J. Groen, Pino J. Poddighe, René J.P. Musters, Johan van Meerloo, Sonja Zweegman, Marloes E.C. Broekmans, Andries C. Bloem, Jeroen F. van Velzen, Berris van Kessel, Inger S. Nijhof, Kris A. Frerichs, and Jakub Krejcik
- Abstract
Daratumumab-mediated CD38 reduction on NK cells is abrogated by depleting monocytes from PBMCs.
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- 2023
41. Preclinical evidence for an effective therapeutic activity of FL118, a novel survivin inhibitor, in patients with relapsed/refractory multiple myeloma
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Susan E. van Hal-van Veen, Hilma J. van der Horst, Joost D. de Bruijn, Fengzhi Li, Richard W.J. Groen, Huipin Yuan, Lisa C. Holthof, Henk M. Lokhorst, Marijke Buijze, Niels W.C.J. van de Donk, Ruud W.J. Ruiter, Sonja Zweegman, Morten Andersen, Tuna Mutis, VU University medical center, Hematology, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, and Hematology laboratory
- Subjects
Oncology ,medicine.medical_specialty ,Benzodioxoles ,business.industry ,Survivin ,Indolizines ,Hematology ,medicine.disease ,Text mining ,Internal medicine ,Relapsed refractory ,medicine ,Humans ,In patient ,Multiple Myeloma ,Online Only Articles ,business ,Multiple myeloma - Published
- 2019
42. Phase II study of carfilzomib, thalidomide, and low-dose dexamethasone as induction and consolidation in newly diagnosed, transplant eligible patients with multiple myeloma; the Carthadex trial
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Pieter Sonneveld, Henk M. Lokhorst, Bronno van der Holt, Emelie Asselbergs, Marie José Kersten, Okke de Weerdt, Marinus van Marwijk Kooy, Edo Vellenga, Monique C. Minnema, Sarah Lonergan, Annemiek Broijl, Sonja Zweegman, Antonio Palumbo, Ruth Wester, Hematology, CCA - Cancer Treatment and quality of life, CCA - Cancer Treatment and Quality of Life, and Clinical Haematology
- Subjects
Adult ,Male ,Melphalan ,medicine.medical_specialty ,Kaplan-Meier Estimate ,Gastroenterology ,Article ,Plasma Cell Disorders ,Dexamethasone ,Translocation, Genetic ,Medication Adherence ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Autologous stem-cell transplantation ,Median follow-up ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Journal Article ,medicine ,Humans ,Multiple myeloma ,Aged ,business.industry ,Remission Induction ,Consolidation Chemotherapy ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Carfilzomib ,Thalidomide ,Treatment Outcome ,Editorial ,chemistry ,Female ,Multiple Myeloma ,business ,Oligopeptides ,Biomarkers ,030215 immunology ,medicine.drug - Abstract
This is a phase II dose escalation trial of carfilzomib in combination with thalidomide and dexamethasone for induction and consolidation in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The results of four dose levels are reported. Induction therapy consisted of four cycles of carfilzomib 20/27 mg/m2 (n=50), 20/36 mg/m2 (n=20), 20/45 mg/m2 (n=21), and 20/56 mg/m2 (n=20) on days 1, 2, 8, 9, 15, 16 of a 28-day cycle; thalidomide 200 mg on day 1 through 28 and dexamethasone 40 mg weekly. Induction therapy was followed by high-dose melphalan and autologous stem cell transplantation and consolidation therapy with four cycles of carfilzomib, thalidomide and dexamethasone in the same schedule except a lower dose of thalidomide (50 mg). Very good partial response rate or better and complete response rate or better after induction therapy were 65% and 18%, respectively, increasing to 86% and 63%, respectively, after consolidation therapy. In all cohorts combined, after a median follow up of 58.7 months, median progression-free survival was 58 months (95%CI: 45-67 months). Median overall survival was 83 months (95%CI: 83 months-not reached). Grade 3/4 adverse events consisted mainly of infections, respiratory disorders, skin and vascular disorders in 11%, 8%, 9%, and 9%, respectively. Grade 3 polyneuropathy was only reported in one patient. Cardiac events were limited: grade 3/4 in 5% of patients. Carfilzomib, thalidomide and dexamethasone as induction and consolidation treatment after high-dose melphalan and autologous stem cell transplantation is highly efficacious and safe in transplant-eligible patients with NDMM. This study was registered as #NTR2422 at http://www.trialregister.nl
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- 2019
43. Combined CD28 and 4-1BB costimulation potentiates affinity-tuned chimeric antigen receptor-engineered t cells
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Maria Themeli, Joost D. de Bruijn, Richard W.J. Groen, Esther Drent, Sonja Zweegman, Renée Poels, Ruud W.J. Ruiter, Huipin Yuan, Tuna Mutis, Henk M. Lokhorst, Michel Sadelain, Niels W.C.J. van de Donk, Hematology laboratory, CCA - Cancer biology and immunology, AII - Cancer immunology, and Hematology
- Subjects
0301 basic medicine ,Cancer Research ,T-Lymphocytes ,medicine.medical_treatment ,Genetic Vectors ,Receptors, Antigen, T-Cell ,Lymphocyte Activation ,Immunotherapy, Adoptive ,Article ,Epitope ,Mice ,Tumor Necrosis Factor Receptor Superfamily, Member 9 ,03 medical and health sciences ,0302 clinical medicine ,CD28 Antigens ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,Gene Order ,medicine ,Animals ,Humans ,Receptor ,Receptors, Chimeric Antigen ,Chemistry ,CD28 ,Immunotherapy ,Xenograft Model Antitumor Assays ,Chimeric antigen receptor ,Cell biology ,Disease Models, Animal ,Phenotype ,Retroviridae ,Treatment Outcome ,030104 developmental biology ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cytokines ,Cytokine secretion ,Genetic Engineering ,Multiple Myeloma ,Immunologic Memory ,Signal Transduction ,Single-Chain Antibodies - Abstract
Purpose: Targeting nonspecific, tumor-associated antigens (TAA) with chimeric antigen receptors (CAR) requires specific attention to restrict possible detrimental on-target/off-tumor effects. A reduced affinity may direct CAR-engineered T (CAR-T) cells to tumor cells expressing high TAA levels while sparing low expressing normal tissues. However, decreasing the affinity of the CAR-target binding may compromise the overall antitumor effects. Here, we demonstrate the prime importance of the type of intracellular signaling on the function of low-affinity CAR-T cells. Experimental Design: We used a series of single-chain variable fragments (scFv) with five different affinities targeting the same epitope of the multiple myeloma–associated CD38 antigen. The scFvs were incorporated in three different CAR costimulation designs and we evaluated the antitumor functionality and off-tumor toxicity of the generated CAR-T cells in vitro and in vivo. Results: We show that the inferior cytotoxicity and cytokine secretion mediated by CD38 CARs of very low–affinity (Kd < 1.9 × 10−6 mol/L) bearing a 4-1BB intracellular domain can be significantly improved when a CD28 costimulatory domain is used. Additional 4-1BB signaling mediated by the coexpression of 4-1BBL provided the CD28-based CD38 CAR-T cells with superior proliferative capacity, preservation of a central memory phenotype, and significantly improved in vivo antitumor function, while preserving their ability to discriminate target antigen density. Conclusions: A combinatorial costimulatory design allows the use of very low–affinity binding domains (Kd < 1 μmol/L) for the construction of safe but also optimally effective CAR-T cells. Thus, very-low-affinity scFvs empowered by selected costimulatory elements can enhance the clinical potential of TAA-targeting CARs.
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- 2019
44. Lenalidomide versus bortezomib maintenance after frontline autologous stem cell transplantation for multiple myeloma
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Markus Munder, Hartmut Goldschmidt, Hans Salwender, Marc S. Raab, Jana Schlenzka, Martin Goerner, Marc-Andrea Baertsch, Martin Hoffmann, Peter Brossart, Dirk Hose, Anna Jauch, Jan Dürig, Stephan Fuhrmann, Steffen Luntz, Christina Kunz, Jens Hillengaß, Hans-Walter Lindemann, Kai Neben, Elias K. Mai, Henk M. Lokhorst, Thomas Hielscher, Ulrich Dührsen, Igor Wolfgang Blau, Hans Martin, Mathias Hänel, Pieter Sonneveld, Christof Scheid, Katja Weisel, Uta Bertsch, Helga Bernhard, Anja Seckinger, Britta Besemer, German-Speaking Myeloma Multicenter Group (GMMG), Hematology, Basic (bio-) Medical Sciences, and Anatomy and neurosciences
- Subjects
Oncology ,Male ,medicine.medical_specialty ,Phase iii trials ,Hematopoietic Stem Cell Transplantation/methods ,Transplantation, Autologous/methods ,Medizin ,Myeloma ,Antineoplastic Agents ,lcsh:RC254-282 ,Transplantation, Autologous ,Article ,Maintenance Chemotherapy ,Bortezomib ,Autologous stem-cell transplantation ,Medical research ,Internal medicine ,medicine ,Internal Medicine ,Humans ,Immunologic Factors ,In patient ,ddc:610 ,Lenalidomide ,Multiple myeloma ,Retrospective Studies ,business.industry ,hematology ,Antineoplastic Agents/therapeutic use ,Hematopoietic Stem Cell Transplantation ,Maintenance Chemotherapy/methods ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunologic Factors/therapeutic use ,Clinical trial ,Multiple Myeloma/therapy ,Lenalidomide/therapeutic use ,Cohort ,Bortezomib/therapeutic use ,Female ,business ,Multiple Myeloma ,medicine.drug - Abstract
Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1–21 of 28 day cycles) followed by 10–15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with n = 54 vs. BTZ: n = 84), LEN MT significantly improved PFS (HR = 0.61, p = 0.04) but not OS (HR = 0.46, p = 0.09). In conclusion, the significant PFS benefit after eliminating the impact of different tandem ASCT rates supports the current standard of LEN MT after ASCT.
- Published
- 2021
45. CD38-targeting antibodies in multiple myeloma
- Author
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Noemi Anna Nagy, Pieter L Lindenbergh, Maria Themeli, Sonja Zweegman, Henk M. Lokhorst, Richard W.J. Groen, Patty Bosman, Jhon Marin Soto, Louise Nieuwenhuis, Tuna Mutis, Inger S. Nijhof, Niels W.C.J. van de Donk, Claudia Stege, Kristine A Frerichs, Marloes E.C. Broekmans, Hematology laboratory, CCA - Cancer biology and immunology, AII - Cancer immunology, Internal medicine, and Hematology
- Subjects
Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,CD38 ,Antibodies, Monoclonal, Humanized ,Dexamethasone ,03 medical and health sciences ,0302 clinical medicine ,Antigens, Neoplasm ,Internal medicine ,medicine ,Overall survival ,Immunology and Allergy ,Animals ,Humans ,Molecular Targeted Therapy ,Multiple myeloma ,Isatuximab ,biology ,business.industry ,Daratumumab ,Antibodies, Monoclonal ,Immunotherapy ,medicine.disease ,ADP-ribosyl Cyclase 1 ,Survival Analysis ,Injection Site Reaction ,Patient Outcome Assessment ,Hematological malignancy ,030220 oncology & carcinogenesis ,biology.protein ,Drug Therapy, Combination ,Antibody ,business ,Multiple Myeloma ,030215 immunology - Abstract
INTRODUCTION: Multiple myeloma (MM) is generally an incurable hematological malignancy with heterogeneous overall survival rates ranging from a few months to more than 10 years. Survival is especially poor for patients who developed disease that is refractory to immunomodulatory drugs and proteasome inhibitors. Areas covered: This review will discuss the importance of CD38-targeting antibodies for the treatment of MM patients to improve their outcome. Expert commentary: Intense immuno-oncological laboratory research has resulted in the development of functionally active monoclonal antibodies against cell surface markers present on MM cells. In this respect, CD38-targeting antibodies such as daratumumab, MOR202, and isatuximab, have high single agent activity in heavily pretreated MM patients by virtue of their pleiotropic mechanisms of action including Fc-dependent effector mechanisms and immunomodulatory activities. Importantly, CD38-targeting antibodies are well tolerated, with infusion reactions as most frequent adverse event. Altogether, this makes them attractive combination partners with other anti-MM agents. Daratumumab is already approved as monotherapy and in combination with lenalidomide-dexamethasone as well as bortezomib-dexamethasone in pretreated MM patients. Furthermore, results from studies evaluating CD38-targeting antibodies in newly diagnosed MM patients are also promising, indicating that CD38-targeting antibodies will be broadly used in MM, resulting in further improvements in survival.
- Published
- 2018
46. Bortezomib before and after high-dose therapy in myeloma
- Author
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Marian Stevens-Kroef, M. van Marwijk Kooy, Henk M. Lokhorst, Hans-Walter Lindemann, Anna Potamianou, Gerard M. J. Bos, B. van der Holt, Igor Wolfgang Blau, Annemiek Broijl, Christoph Scheid, Peter Brossart, Pieter Sonneveld, Sonja Zweegman, R. Schaafsma, Sandra Croockewit, Reinier Raymakers, Le Jarari, Ulrich Duehrsen, H Salwender, Jens Hillengass, Dirk Hose, Elias K. Mai, Anna Jauch, Marc-Steffen Raab, Michael Pfreundschuh, Thomas Hielscher, Paula F. Ypma, Marie-Jose Kersten, Katja Weisel, Edo Vellenga, H. Goldschmidt, Uta Bertsch, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Hematologie (9), Hematology, CCA - Cancer immunology, CCA - Imaging, CCA - Biomarkers, CCA - Clinical Therapy Development, CCA - Evaluation of Cancer Care, CCA - Target Discovery & Preclinial Therapy Development, Anatomy and neurosciences, CCA - Cancer Treatment and Quality of Life, Clinical Haematology, AII - Amsterdam institute for Infection and Immunity, and AII - Inflammatory diseases
- Subjects
Male ,Melphalan ,2ND PRIMARY MALIGNANCIES ,Cancer Research ,DIAGNOSED MULTIPLE-MYELOMA ,Medizin ,PLUS DEXAMETHASONE ,Bortezomib ,0302 clinical medicine ,Autologous stem-cell transplantation ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,Multiple myeloma ,INTERGROUPE FRANCOPHONE ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Prognosis ,Progression-Free Survival ,Thalidomide ,Oncology ,030220 oncology & carcinogenesis ,DEXAMETHASONE COMBINATION ,DELETION 17P ,Female ,Multiple Myeloma ,medicine.drug ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Adult ,medicine.medical_specialty ,Adolescent ,Urology ,MAINTENANCE TREATMENT ,Transplantation, Autologous ,Young Adult ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,medicine ,Humans ,Progression-free survival ,Aged ,Chromosome Aberrations ,business.industry ,STEM-CELL TRANSPLANTATION ,STAGING SYSTEM ,medicine.disease ,RANDOMIZED-TRIAL ,Surgery ,Transplantation ,business ,Follow-Up Studies ,030215 immunology - Abstract
The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR) = 0.76, 95% confidence interval (95% CI) of 0.65-0.89, P = 0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR = 0.89, 95% CI: 0.74-1.08, P = 0.24). The incidence of SPM were similar between the two arms (7% each, P = 0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size >= 10%) and renal impairment at baseline (serum creatinine > 2 mg dl(-1)) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR = 1.02, P = 0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.
- Published
- 2018
47. Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab
- Author
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Torben Plesner, René J. P. Musters, Berris van Kessel, Jeroen F. van Velzen, A. Kate Sasser, Pino J. Poddighe, Marloes E.C. Broekmans, Tuna Mutis, Inger S. Nijhof, Henk M. Lokhorst, Jakub Krejcik, Richard W.J. Groen, Kris A. Frerichs, Sonja Zweegman, Niels W.C.J. van de Donk, Andries C. Bloem, Johan van Meerloo, Christopher Chiu, Hematology laboratory, Hematology, CCA - Cancer biology and immunology, AII - Cancer immunology, Physiology, Human genetics, ACS - Microcirculation, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
Male ,Cancer Research ,T-Lymphocytes ,CD38 ,Dexamethasone ,Monocytes ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Lenalidomide ,Multiple myeloma ,Isatuximab ,B-Lymphocytes ,biology ,Antibodies, Monoclonal ,B-Lymphocytes/immunology ,Middle Aged ,Thalidomide ,Gene Expression Regulation, Neoplastic ,Killer Cells, Natural ,Oncology ,030220 oncology & carcinogenesis ,Killer Cells, Natural/immunology ,ADP-ribosyl Cyclase 1/genetics ,Female ,Antibody ,Multiple Myeloma ,Granulocytes/drug effects ,Dexamethasone/administration & dosage ,Trogocytosis ,Multiple Myeloma/drug therapy ,Antibodies, Monoclonal/administration & dosage ,Article ,03 medical and health sciences ,Immune system ,Monocytes/drug effects ,Cell Line, Tumor ,medicine ,Humans ,Aged ,Thalidomide/administration & dosage ,Daratumumab ,medicine.disease ,ADP-ribosyl Cyclase 1 ,Cell culture ,Gene Expression Regulation, Neoplastic/drug effects ,Immunology ,biology.protein ,030215 immunology ,Granulocytes - Abstract
Purpose: Daratumumab treatment results in a marked reduction of CD38 expression on multiple myeloma cells. The aim of this study was to investigate the clinical implications and the underlying mechanisms of daratumumab-mediated CD38 reduction. Experimental Design: We evaluated the effect of daratumumab alone or in combination with lenalidomide-dexamethasone, on CD38 levels of multiple myeloma cells and nontumor immune cells in the GEN501 study (daratumumab monotherapy) and the GEN503 study (daratumumab combined with lenalidomide-dexamethasone). In vitro assays were also performed. Results: In both trials, daratumumab reduced CD38 expression on multiple myeloma cells within hours after starting the first infusion, regardless of depth and duration of the response. In addition, CD38 expression on nontumor immune cells, including natural killer cells, T cells, B cells, and monocytes, was also reduced irrespective of alterations in their absolute numbers during therapy. In-depth analyses revealed that CD38 levels of multiple myeloma cells were only reduced in the presence of complement or effector cells, suggesting that the rapid elimination of CD38high multiple myeloma cells can contribute to CD38 reduction. In addition, we discovered that daratumumab–CD38 complexes and accompanying cell membrane were actively transferred from multiple myeloma cells to monocytes and granulocytes. This process of trogocytosis was also associated with reduced surface levels of some other membrane proteins, including CD49d, CD56, and CD138. Conclusions: Daratumumab rapidly reduced CD38 expression levels, at least in part, through trogocytosis. Importantly, all these effects also occurred in patients with deep and durable responses, thus excluding CD38 reduction alone as a mechanism of daratumumab resistance. The trials were registered at www.clinicaltrials.gov as NCT00574288 (GEN501) and NCT1615029 (GEN503). Clin Cancer Res; 23(24); 7498–511. ©2017 AACR.
- Published
- 2017
48. A Rational Strategy for Reducing On-Target Off-Tumor Effects of CD38-Chimeric Antigen Receptors by Affinity Optimization
- Author
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Regina de Jong-Korlaar, Renée Poels, Huipin Yuan, Anton C.M. Martens, Henk M. Lokhorst, Joost D. de Bruijn, Richard W.J. Groen, Niels W.C.J. van de Donk, Esther Drent, Tuna Mutis, Maria Themeli, Sonja Zweegman, Hematology laboratory, CCA - Cancer biology and immunology, and Hematology
- Subjects
0301 basic medicine ,Recombinant Fusion Proteins ,medicine.medical_treatment ,Antibody Affinity ,Receptors, Antigen, T-Cell ,CD38 ,Lymphocyte Activation ,Immunoglobulin light chain ,Immunotherapy, Adoptive ,Mice ,03 medical and health sciences ,Antigen ,Drug Discovery ,Genetics ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Cytotoxicity ,Molecular Biology ,Pharmacology ,biology ,ADP-ribosyl Cyclase 1 ,Xenograft Model Antitumor Assays ,Molecular biology ,Chimeric antigen receptor ,3. Good health ,Cell biology ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,biology.protein ,Cytokines ,Molecular Medicine ,Original Article ,Antibody ,Multiple Myeloma ,Protein Binding ,Single-Chain Antibodies ,T-Lymphocytes, Cytotoxic - Abstract
Chimeric antigen receptors (CARs) can effectively redirect cytotoxic T cells toward highly expressed surface antigens on tumor cells. The low expression of several tumor-associated antigens (TAAs) on normal tissues, however, hinders their safe targeting by CAR T cells due to on-target/off-tumor effects. Using the multiple myeloma (MM)-associated CD38 antigen as a model system, here, we present a rational approach for effective and tumor-selective targeting of such TAAs. Using “light-chain exchange” technology, we combined the heavy chains of two high-affinity CD38 antibodies with 176 germline light chains and generated ∼124 new antibodies with 10- to >1,000-fold lower affinities to CD38. After categorizing them into three distinct affinity classes, we incorporated the single-chain variable fragments of eight antibodies from each class into new CARs. T cells carrying these CD38-CARs were extensively evaluated for their on-tumor/off-tumor cytotoxicity as well as CD38-dependent proliferation and cytokine production. We identified CD38-CAR T cells of ∼1,000- fold reduced affinity, which optimally proliferated, produced Th1-like cytokines, and effectively lysed CD382+ MM cells, but spared CD38+ healthy hematopoietic cells in vitro and in vivo. Thus, this systematic approach is highly suitable for the generation of optimal CARs for effective and selective targeting of TAAs.
- Published
- 2017
49. High-Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action
- Author
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Torben Plesner, Saad Z. Usmani, Koen Van der Borght, Homer Adams, Greet Vanhoof, Amy Sasser, Henk M. Lokhorst, Tineke Casneuf, Jakub Krejcik, Inger S. Nijhof, Tina Smets, Christopher Chiu, Hugo Ceulemans, Sagar Lonial, Niels W.C.J. van de Donk, Tuna Mutis, Frederik Stevenaert, Yann Abraham, Jaime Bald, Hematology, CCA - Cancer biology and immunology, AII - Cancer immunology, Hematology laboratory, and CCA - Imaging and biomarkers
- Subjects
Antigens, Differentiation, T-Lymphocyte ,CD4-Positive T-Lymphocytes ,0301 basic medicine ,Histology ,Population ,Antineoplastic Agents ,Bone Marrow Cells ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Granzymes ,Immunophenotyping ,Pathology and Forensic Medicine ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,medicine ,Humans ,Mass cytometry ,IL-2 receptor ,education ,education.field_of_study ,medicine.diagnostic_test ,biology ,business.industry ,immune profiling ,Antibodies, Monoclonal ,Daratumumab ,Cell Biology ,Flow Cytometry ,cytometry by time of flight ,ADP-ribosyl Cyclase 1 ,Basophils ,Killer Cells, Natural ,Granzyme B ,030104 developmental biology ,Granzyme ,Immunology ,biology.protein ,CyTOF ,Multiple Myeloma ,business ,030215 immunology - Abstract
Daratumumab is a CD38-targeted human monoclonal antibody with direct anti-myeloma cell mechanisms of action. Flow cytometry in relapsed and/or refractory multiple myeloma (RRMM) patients treated with daratumumab revealed cytotoxic T-cell expansion and reduction of immune-suppressive populations, suggesting immune modulation as an additional mechanism of action. Here, we performed an in-depth analysis of the effects of daratumumab on immune-cell subpopulations using high-dimensional mass cytometry. Whole-blood and bone-marrow baseline and on-treatment samples from RRMM patients who participated in daratumumab monotherapy studies (SIRIUS and GEN501) were evaluated with high-throughput immunophenotyping. In daratumumab-treated patients, the intensity of CD38 marker expression decreased on many immune cells in SIRIUS whole-blood samples. Natural killer (NK) cells were depleted with daratumumab, with remaining NK cells showing increased CD69 and CD127, decreased CD45RA, and trends for increased CD25, CD27, and CD137 and decreased granzyme B. Immune-suppressive population depletion paralleled previous findings, and a newly observed reduction in CD38+ basophils was seen in patients who received monotherapy. After 2 months of daratumumab, the T-cell population in whole-blood samples from responders shifted to a CD8 prevalence with higher granzyme B positivity (P = 0.017), suggesting increased killing capacity and supporting monotherapy-induced CD8+ T-cell activation. High-throughput cytometry immune profiling confirms and builds upon previous flow cytometry data, including comparable CD38 marker intensity on plasma cells, NK cells, monocytes, and B/T cells. Interestingly, a shift toward cytolytic granzyme B+ T cells was also observed and supports adaptive responses in patients that may contribute to depth of response. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.
- Published
- 2019
50. Impact of Fc gamma receptor polymorphisms on efficacy and safety of daratumumab in relapsed/refractory multiple myeloma
- Author
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Tineke Casneuf, Inger S. Nijhof, Alessandro Di Cara, Berris van Kessel, Sagar Lonial, Tuna Mutis, Paul G. Richardson, Niels W.C.J. van de Donk, Sonja Zweegman, Paul W. H. I. Parren, Christopher Chiu, A. Kate Sasser, Henk M. Lokhorst, Saad Z. Usmani, CCA - Cancer biology and immunology, AII - Cancer immunology, Hematology, and Hematology laboratory
- Subjects
Male ,0301 basic medicine ,medicine.medical_treatment ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Multiple myeloma ,Polymorphism, Genetic ,Fcγ receptors ,business.industry ,Receptors, IgG ,Antibodies, Monoclonal ,Daratumumab ,Hematology ,Immunotherapy ,medicine.disease ,daratumumab ,Neoplasm Proteins ,Survival Rate ,multiple myeloma ,030104 developmental biology ,Relapsed refractory ,Fc gamma receptors ,Cancer research ,Fc-Gamma Receptor ,Female ,immunotherapy ,business ,polymorphisms ,030215 immunology - Published
- 2019
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