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1. Sensitive liquid biopsy monitoring correlates with outcome in the prospective international GPOH-DCOG high-risk neuroblastoma RT-qPCR validation study

Author

van Zogchel, Lieke M. J., Decarolis, Boris, van Wezel, Esther M., Zappeij‐Kannegieter, Lily, Gelineau, Nina U., Schumacher‐Kuckelkorn, Roswitha, Simon, Thorsten, Berthold, Frank, van Noesel, Max M., Fiocco, Marta, van der Schoot, C. Ellen, Hero, Barbara, Stutterheim, Janine, and Tytgat, Godelieve A. M.

Published
2024
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9. mRNA Expression Level of ALK in Neuroblastoma Is Associated with Histological Subtype, ALK Mutations and ALK Immunohistochemical Protein Expression.

Author

Bruinsma, Rixt S., Fiocco, Marta F., de Leng, Wendy W. J., Kester, Lennart A., Langenberg, Karin P. S., Tytgat, Godelieve A. M., van Noesel, Max M., Wijnen, Marc H. W. A., van der Steeg, Alida F. W., and de Krijger, Ronald R.

Subjects
NEUROBLASTOMA, PROTEIN expression, TRANSCRIPTOMES, SINGLE nucleotide polymorphisms, IMMUNOHISTOCHEMISTRY
Abstract

ALK is related to poor survival in neuroblastoma patients. We investigated the prognostic relevance of ALK mRNA expression and the relationship with ALK immunohistochemical expression, histological subtype and ALK aberrations. Whole transcriptome sequencing data were available from 54 patients. Overall survival (OS) and event-free survival (EFS) were estimated with Kaplan–Meier's methodology. ALK protein expression was analyzed by immunohistochemistry. ALK aberrations were detected using whole exome sequencing, single nucleotide polymorphism array, next generation sequencing and/or fluorescence in situ hybridization. OS was 74.8% and EFS was 60%. ALK mRNA expression was not associated with OS (HR 1.127, 95% CI (0.812–1.854), p = 0.331) and adjusted EFS (HR 1.134, 95% CI (0.783–1.644), p = 0.505), but was associated with histological subtype (OR 1.914, 95% CI (1.083–3.382), p = 0.025) and ALK protein expression (negative versus weak: OR 2.829, 95% CI (1.290–6.204), p = 0.009) (negative versus moderate/strong: OR 2.934, 95% CI (0.889–9.679), p = 0.077). ALK mutated tumors had significantly higher ALK mRNA expression than non-mutated tumors (p < 0.001). MYCN-amplified neuroblastomas have higher MYCN mRNA expression (p ≤ 0.001), but not ALK mRNA expression (p = 0.553). ALK mRNA expression is higher in ALK mutated neuroblastomas and is associated with poorer differentiation degree and higher protein expression. ALK mRNA expression is not significantly associated with OS and EFS. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy

Author

Wienke, Judith, Visser, Lindy L, Kholosy, Waleed M, Keller, Kaylee M, Barisa, Marta, Poon, Evon, Munnings-Tomes, Sophie, Himsworth, Courtney, Calton, Elizabeth, Rodriguez, Ana, Bernardi, Ronald, van den Ham, Femke, van Hooff, Sander R, Matser, Yvette A H, Tas, Michelle L, Langenberg, Karin P S, Lijnzaad, Philip, Borst, Anne L, Zappa, Elisa, Bergsma, Francisca J, Strijker, Josephine G M, Verhoeven, Bronte M, Mei, Shenglin, Kramdi, Amira, Restuadi, Restuadi, Sanchez-Bernabeu, Alvaro, Cornel, Annelisa M, Holstege, Frank C P, Gray, Juliet C, Tytgat, Godelieve A M, Scheijde-Vermeulen, Marijn A, Wijnen, Marc H W A, Dierselhuis, Miranda P, Straathof, Karin, Behjati, Sam, Wu, Wei, Heck, Albert J R, Koster, Jan, Nierkens, Stefan, Janoueix-Lerosey, Isabelle, de Krijger, Ronald R, Baryawno, Ninib, Chesler, Louis, Anderson, John, Caron, Hubert N, Margaritis, Thanasis, van Noesel, Max M, Molenaar, Jan J, Wienke, Judith, Visser, Lindy L, Kholosy, Waleed M, Keller, Kaylee M, Barisa, Marta, Poon, Evon, Munnings-Tomes, Sophie, Himsworth, Courtney, Calton, Elizabeth, Rodriguez, Ana, Bernardi, Ronald, van den Ham, Femke, van Hooff, Sander R, Matser, Yvette A H, Tas, Michelle L, Langenberg, Karin P S, Lijnzaad, Philip, Borst, Anne L, Zappa, Elisa, Bergsma, Francisca J, Strijker, Josephine G M, Verhoeven, Bronte M, Mei, Shenglin, Kramdi, Amira, Restuadi, Restuadi, Sanchez-Bernabeu, Alvaro, Cornel, Annelisa M, Holstege, Frank C P, Gray, Juliet C, Tytgat, Godelieve A M, Scheijde-Vermeulen, Marijn A, Wijnen, Marc H W A, Dierselhuis, Miranda P, Straathof, Karin, Behjati, Sam, Wu, Wei, Heck, Albert J R, Koster, Jan, Nierkens, Stefan, Janoueix-Lerosey, Isabelle, de Krijger, Ronald R, Baryawno, Ninib, Chesler, Louis, Anderson, John, Caron, Hubert N, Margaritis, Thanasis, van Noesel, Max M, and Molenaar, Jan J

Abstract

Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. Since novel and improved immunotherapies may fill this need, we dissect the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 24 tumors (10 pre- and 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated by natural killer (NK), T and B cells, and immunosuppressive myeloid populations. NK cells show reduced cytotoxicity and T cells have a dysfunctional profile. Interaction analysis reveals a vast immunoregulatory network and identifies NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduces neuroblastoma growth, with complete responses (CR) in vivo. Moreover, addition of TIGIT+PD-L1 blockade to standard relapse treatment in a chemotherapy-resistant Th-ALK F1174L/MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative analysis provides promising targets and a rationale for immunotherapeutic combination strategies.

Published
2024

12. Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy

Author

Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Afd Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Pharmaceutics, Wienke, Judith, Visser, Lindy L, Kholosy, Waleed M, Keller, Kaylee M, Barisa, Marta, Poon, Evon, Munnings-Tomes, Sophie, Himsworth, Courtney, Calton, Elizabeth, Rodriguez, Ana, Bernardi, Ronald, van den Ham, Femke, van Hooff, Sander R, Matser, Yvette A H, Tas, Michelle L, Langenberg, Karin P S, Lijnzaad, Philip, Borst, Anne L, Zappa, Elisa, Bergsma, Francisca J, Strijker, Josephine G M, Verhoeven, Bronte M, Mei, Shenglin, Kramdi, Amira, Restuadi, Restuadi, Sanchez-Bernabeu, Alvaro, Cornel, Annelisa M, Holstege, Frank C P, Gray, Juliet C, Tytgat, Godelieve A M, Scheijde-Vermeulen, Marijn A, Wijnen, Marc H W A, Dierselhuis, Miranda P, Straathof, Karin, Behjati, Sam, Wu, Wei, Heck, Albert J R, Koster, Jan, Nierkens, Stefan, Janoueix-Lerosey, Isabelle, de Krijger, Ronald R, Baryawno, Ninib, Chesler, Louis, Anderson, John, Caron, Hubert N, Margaritis, Thanasis, van Noesel, Max M, Molenaar, Jan J, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Afd Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Pharmaceutics, Wienke, Judith, Visser, Lindy L, Kholosy, Waleed M, Keller, Kaylee M, Barisa, Marta, Poon, Evon, Munnings-Tomes, Sophie, Himsworth, Courtney, Calton, Elizabeth, Rodriguez, Ana, Bernardi, Ronald, van den Ham, Femke, van Hooff, Sander R, Matser, Yvette A H, Tas, Michelle L, Langenberg, Karin P S, Lijnzaad, Philip, Borst, Anne L, Zappa, Elisa, Bergsma, Francisca J, Strijker, Josephine G M, Verhoeven, Bronte M, Mei, Shenglin, Kramdi, Amira, Restuadi, Restuadi, Sanchez-Bernabeu, Alvaro, Cornel, Annelisa M, Holstege, Frank C P, Gray, Juliet C, Tytgat, Godelieve A M, Scheijde-Vermeulen, Marijn A, Wijnen, Marc H W A, Dierselhuis, Miranda P, Straathof, Karin, Behjati, Sam, Wu, Wei, Heck, Albert J R, Koster, Jan, Nierkens, Stefan, Janoueix-Lerosey, Isabelle, de Krijger, Ronald R, Baryawno, Ninib, Chesler, Louis, Anderson, John, Caron, Hubert N, Margaritis, Thanasis, van Noesel, Max M, and Molenaar, Jan J

Published
2024

13. Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy

Author

CTI Nierkens, Cancer, Infection & Immunity, CTI Research, Pathologie Pathologen staf, Onderzoek Beeld, Wienke, Judith, Visser, Lindy L, Kholosy, Waleed M, Keller, Kaylee M, Barisa, Marta, Poon, Evon, Munnings-Tomes, Sophie, Himsworth, Courtney, Calton, Elizabeth, Rodriguez, Ana, Bernardi, Ronald, van den Ham, Femke, van Hooff, Sander R, Matser, Yvette A H, Tas, Michelle L, Langenberg, Karin P S, Lijnzaad, Philip, Borst, Anne L, Zappa, Elisa, Bergsma, Francisca J, Strijker, Josephine G M, Verhoeven, Bronte M, Mei, Shenglin, Kramdi, Amira, Restuadi, Restuadi, Sanchez-Bernabeu, Alvaro, Cornel, Annelisa M, Holstege, Frank C P, Gray, Juliet C, Tytgat, Godelieve A M, Scheijde-Vermeulen, Marijn A, Wijnen, Marc H W A, Dierselhuis, Miranda P, Straathof, Karin, Behjati, Sam, Wu, Wei, Heck, Albert J R, Koster, Jan, Nierkens, Stefan, Janoueix-Lerosey, Isabelle, de Krijger, Ronald R, Baryawno, Ninib, Chesler, Louis, Anderson, John, Caron, Hubert N, Margaritis, Thanasis, van Noesel, Max M, Molenaar, Jan J, CTI Nierkens, Cancer, Infection & Immunity, CTI Research, Pathologie Pathologen staf, Onderzoek Beeld, Wienke, Judith, Visser, Lindy L, Kholosy, Waleed M, Keller, Kaylee M, Barisa, Marta, Poon, Evon, Munnings-Tomes, Sophie, Himsworth, Courtney, Calton, Elizabeth, Rodriguez, Ana, Bernardi, Ronald, van den Ham, Femke, van Hooff, Sander R, Matser, Yvette A H, Tas, Michelle L, Langenberg, Karin P S, Lijnzaad, Philip, Borst, Anne L, Zappa, Elisa, Bergsma, Francisca J, Strijker, Josephine G M, Verhoeven, Bronte M, Mei, Shenglin, Kramdi, Amira, Restuadi, Restuadi, Sanchez-Bernabeu, Alvaro, Cornel, Annelisa M, Holstege, Frank C P, Gray, Juliet C, Tytgat, Godelieve A M, Scheijde-Vermeulen, Marijn A, Wijnen, Marc H W A, Dierselhuis, Miranda P, Straathof, Karin, Behjati, Sam, Wu, Wei, Heck, Albert J R, Koster, Jan, Nierkens, Stefan, Janoueix-Lerosey, Isabelle, de Krijger, Ronald R, Baryawno, Ninib, Chesler, Louis, Anderson, John, Caron, Hubert N, Margaritis, Thanasis, van Noesel, Max M, and Molenaar, Jan J

Published
2024

16. Targeted therapies in children with renal cell carcinoma (RCC): An International Society of Pediatric Oncology—Renal Tumor Study Group (SIOP‐RTSG)‐related retrospective descriptive study

Author

Sprokkerieft, Julia, primary, van der Beek, Justine N., additional, Spreafico, Filippo, additional, Selle, Barbara, additional, Thebaud, Estelle, additional, Chowdhury, Tanzina, additional, Brok, Jesper, additional, Ottóffy, Gábor, additional, Sun, Xiaofei, additional, Ramírez Villar, Gema L., additional, Sagoyan, Garik, additional, Segers, Heidi, additional, Doganis, Dimitrios, additional, Serra, Annalisa, additional, Lemelle, Lauriane, additional, Graf, Norbert, additional, Verschuur, Arnauld C., additional, Tytgat, Godelieve A. M., additional, and van den Heuvel‐Eibrink, Marry M., additional

Published
2023
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19. An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity

Author

Calandrini, Camilla, Schutgens, Frans, Oka, Rurika, Margaritis, Thanasis, Candelli, Tito, Mathijsen, Luka, Ammerlaan, Carola, van Ineveld, Ravian L., Derakhshan, Sepide, de Haan, Sanne, Dolman, Emmy, Lijnzaad, Philip, Custers, Lars, Begthel, Harry, Kerstens, Hindrik H. D., Visser, Lindy L., Rookmaaker, Maarten, Verhaar, Marianne, Tytgat, Godelieve A. M., Kemmeren, Patrick, de Krijger, Ronald R., Al-Saadi, Reem, Pritchard-Jones, Kathy, Kool, Marcel, Rios, Anne C., van den Heuvel-Eibrink, Marry M., Molenaar, Jan J., van Boxtel, Ruben, Holstege, Frank C. P., Clevers, Hans, and Drost, Jarno

Published
2020
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20. Novel Circulating Hypermethylated RASSF1A ddPCR for Liquid Biopsies in Patients With Pediatric Solid Tumors

Author

van Zogchel, Lieke M. J., Lak, Nathalie S. M., Verhagen, Onno J. H. M., Tissoudali, Ahmed, Gussmalla Nuru, Mohammed, Gelineau, Nina U., Zappeij-Kannengieter, Lily, Javadi, Ahmad, Zijtregtop, Eline A. M., Merks, Johannes H. M., van den Heuvel-Eibrink, Marry, Schouten-van Meeteren, Antoinette Y. N., Stutterheim, Janine, van der Schoot, C. Ellen, and Tytgat, Godelieve A. M.

Published
2021
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21. Cell-Free RNA from Plasma in Patients with Neuroblastoma: Exploring the Technical and Clinical Potential

Author

Lak, Nathalie S M, Seijger, Anne, van Zogchel, Lieke M J, Gelineau, Nina U, Javadi, Ahmad, Zappeij-Kannegieter, Lily, Bongiovanni, Laura, Andriessen, Anneloes, Stutterheim, Janine, van der Schoot, C Ellen, de Bruin, Alain, Tytgat, Godelieve A M, Lak, Nathalie S M, Seijger, Anne, van Zogchel, Lieke M J, Gelineau, Nina U, Javadi, Ahmad, Zappeij-Kannegieter, Lily, Bongiovanni, Laura, Andriessen, Anneloes, Stutterheim, Janine, van der Schoot, C Ellen, de Bruin, Alain, and Tytgat, Godelieve A M

Abstract

Neuroblastoma affects mostly young children, bearing a high morbidity and mortality. Liquid biopsies, e.g., molecular analysis of circulating tumor-derived nucleic acids in blood, offer a minimally invasive diagnostic modality. Cell-free RNA (cfRNA) is released by all cells, especially cancer. It circulates in blood packed in extracellular vesicles (EV) or attached to proteins. We studied the feasibility of analyzing cfRNA and EV, isolated by size exclusion chromatography (SEC), from platelet-poor plasma from healthy controls ( n = 40) and neuroblastoma patients with localized ( n = 10) and metastatic disease ( n = 30). The mRNA content was determined using several multiplex droplet digital PCR (ddPCR) assays for a neuroblastoma-specific gene panel ( PHOX2B, TH, CHRNA3) and a cell cycle regulation panel ( E2F1, CDC6, ATAD2, H2AFZ, MCM2, DHFR). We applied corrections for the presence of platelets. We demonstrated that neuroblastoma-specific markers were present in plasma from 14/30 patients with metastatic disease and not in healthy controls and patients with localized disease. Most cell cycle markers had a higher expression in patients. The mRNA markers were mostly present in the EV-enriched SEC fractions. In conclusion, cfRNA can be isolated from plasma and EV and analyzed using multiplex ddPCR. cfRNA is an interesting novel liquid biopsy-based target to explore further.

Published
2023

22. Cell-Free RNA from Plasma in Patients with Neuroblastoma: Exploring the Technical and Clinical Potential

Author

Pathobiologie, Dep Biomolecular Health Sciences, Lak, Nathalie S M, Seijger, Anne, van Zogchel, Lieke M J, Gelineau, Nina U, Javadi, Ahmad, Zappeij-Kannegieter, Lily, Bongiovanni, Laura, Andriessen, Anneloes, Stutterheim, Janine, van der Schoot, C Ellen, de Bruin, Alain, Tytgat, Godelieve A M, Pathobiologie, Dep Biomolecular Health Sciences, Lak, Nathalie S M, Seijger, Anne, van Zogchel, Lieke M J, Gelineau, Nina U, Javadi, Ahmad, Zappeij-Kannegieter, Lily, Bongiovanni, Laura, Andriessen, Anneloes, Stutterheim, Janine, van der Schoot, C Ellen, de Bruin, Alain, and Tytgat, Godelieve A M

Published
2023

23. Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors

Author

CMM Groep Cuppen, Groep Holstege, Pathologie Pathologen staf, Cancer, van Zogchel, Lieke M J, Lak, Nathalie S M, Gelineau, Nina U, Sergeeva, Irina, Stelloo, Ellen, Swennenhuis, Joost, Feitsma, Harma, van Min, Max, Splinter, Erik, Bleijs, Margit, Groot Koerkamp, Marian, Breunis, Willemijn, Meister, Michael Torsten, Kholossy, Waleed Hassan, Holstege, Frank C P, Molenaar, Jan J, de Leng, Wendy W J, Stutterheim, Janine, van der Schoot, C Ellen, Tytgat, Godelieve A M, CMM Groep Cuppen, Groep Holstege, Pathologie Pathologen staf, Cancer, van Zogchel, Lieke M J, Lak, Nathalie S M, Gelineau, Nina U, Sergeeva, Irina, Stelloo, Ellen, Swennenhuis, Joost, Feitsma, Harma, van Min, Max, Splinter, Erik, Bleijs, Margit, Groot Koerkamp, Marian, Breunis, Willemijn, Meister, Michael Torsten, Kholossy, Waleed Hassan, Holstege, Frank C P, Molenaar, Jan J, de Leng, Wendy W J, Stutterheim, Janine, van der Schoot, C Ellen, and Tytgat, Godelieve A M

Published
2023

24. Correction to: [ 18F]mFBG PET‑CT for detection and localisation of neuroblastoma: a prospective pilot study (European Journal of Nuclear Medicine and Molecular Imaging, (2023), 50, 4, (1146-1157), 10.1007/s00259-022-06063-6)

Author

Radionuclide Apotheek, Cancer, MS Radiologie, Brain, Fysica Radiologie, Onderzoek Beeld, Researchgr. Nucleaire Geneeskunde, Samim, Atia, Blom, Thomas, Poot, Alex J, Windhorst, Albert D, Fiocco, Marta, Tolboom, Nelleke, Braat, Arthur J A T, Viol, Sebastiaan L Meyer, van Rooij, Rob, van Noesel, Max M, Lam, Marnix G E H, Tytgat, Godelieve A M, de Keizer, Bart, Radionuclide Apotheek, Cancer, MS Radiologie, Brain, Fysica Radiologie, Onderzoek Beeld, Researchgr. Nucleaire Geneeskunde, Samim, Atia, Blom, Thomas, Poot, Alex J, Windhorst, Albert D, Fiocco, Marta, Tolboom, Nelleke, Braat, Arthur J A T, Viol, Sebastiaan L Meyer, van Rooij, Rob, van Noesel, Max M, Lam, Marnix G E H, Tytgat, Godelieve A M, and de Keizer, Bart

Published
2023

25. Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma

Author

Onderzoek Beeld, Cancer, Lak, Nathalie S M, van Zogchel, Lieke M J, Zappeij-Kannegieter, Lily, Javadi, Ahmad, van Paemel, Ruben, Vandeputte, Charlotte, De Preter, Katleen, De Wilde, Bram, Chicard, Mathieu, Iddir, Yasmine, Schleiermacher, Gudrun, Ruhen, Olivia, Shipley, Janet, Fiocco, Marta, Merks, Johannes H M, van Noesel, Max M, van der Schoot, C Ellen, Tytgat, Godelieve A M, Stutterheim, Janine, Onderzoek Beeld, Cancer, Lak, Nathalie S M, van Zogchel, Lieke M J, Zappeij-Kannegieter, Lily, Javadi, Ahmad, van Paemel, Ruben, Vandeputte, Charlotte, De Preter, Katleen, De Wilde, Bram, Chicard, Mathieu, Iddir, Yasmine, Schleiermacher, Gudrun, Ruhen, Olivia, Shipley, Janet, Fiocco, Marta, Merks, Johannes H M, van Noesel, Max M, van der Schoot, C Ellen, Tytgat, Godelieve A M, and Stutterheim, Janine

Published
2023

26. Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors

Author

van Zogchel, Lieke M J, Lak, Nathalie S M; https://orcid.org/0000-0003-3743-8826, Gelineau, Nina U, Sergeeva, Irina, Stelloo, Ellen, Swennenhuis, Joost, Feitsma, Harma, van Min, Max, Splinter, Erik, Bleijs, Margit, Groot Koerkamp, Marian, Breunis, Willemijn, Meister, Michael Torsten, Kholossy, Waleed Hassan, Holstege, Frank C P; https://orcid.org/0000-0002-8090-5146, Molenaar, Jan J, de Leng, Wendy W J, Stutterheim, Janine; https://orcid.org/0000-0002-9828-0834, van der Schoot, C Ellen, Tytgat, Godelieve A M, van Zogchel, Lieke M J, Lak, Nathalie S M; https://orcid.org/0000-0003-3743-8826, Gelineau, Nina U, Sergeeva, Irina, Stelloo, Ellen, Swennenhuis, Joost, Feitsma, Harma, van Min, Max, Splinter, Erik, Bleijs, Margit, Groot Koerkamp, Marian, Breunis, Willemijn, Meister, Michael Torsten, Kholossy, Waleed Hassan, Holstege, Frank C P; https://orcid.org/0000-0002-8090-5146, Molenaar, Jan J, de Leng, Wendy W J, Stutterheim, Janine; https://orcid.org/0000-0002-9828-0834, van der Schoot, C Ellen, and Tytgat, Godelieve A M

Abstract

BACKGROUND Liquid biopsies combine minimally invasive sample collection with sensitive detection of residual disease. Pediatric malignancies harbor tumor-driving copy number alterations or fusion genes, rather than recurrent point mutations. These regions contain tumor-specific DNA breakpoint sequences. We investigated the feasibility to use these breakpoints to design patient-specific markers to detect tumor-derived cell-free DNA (cfDNA) in plasma from patients with pediatric solid tumors. MATERIALS AND METHODS Regions of interest (ROI) were identified through standard clinical diagnostic pipelines, using SNP array for CNAs, and FISH or RT-qPCR for fusion genes. Using targeted locus amplification (TLA) on tumor organoids grown from tumor material or targeted locus capture (TLC) on FFPE material, ROI-specific primers and probes were designed, which were used to design droplet digital PCR (ddPCR) assays. cfDNA from patient plasma at diagnosis and during therapy was analyzed. RESULTS TLA was performed on material from 2 rhabdomyosarcoma, 1 Ewing sarcoma and 3 neuroblastoma. FFPE-TLC was performed on 8 neuroblastoma tumors. For all patients, at least one patient-specific ddPCR was successfully designed and in all diagnostic plasma samples the patient-specific markers were detected. In the rhabdomyosarcoma and Ewing sarcoma patients, all samples after start of therapy were negative. In neuroblastoma patients, presence of patient-specific markers in cfDNA tracked tumor burden, decreasing during induction therapy, disappearing at complete remission and re-appearing at relapse. CONCLUSION We demonstrate the feasibility to determine tumor-specific breakpoints using TLA/TLC in different pediatric solid tumors and use these for analysis of cfDNA from plasma. Considering the high prevalence of CNAs and fusion genes in pediatric solid tumors, this approach holds great promise and deserves further study in a larger cohort with standardized plasma sampling protocols.

Published
2023

27. Targeted therapies in children with renal cell carcinoma (RCC): An International Society of Pediatric Oncology— Renal Tumor Study Group (SIOP-RTSG)-related retrospective descriptive study.

Author

Sprokkerieft, Julia, van der Beek, Justine N., Spreafico, Filippo, Selle, Barbara, Thebaud, Estelle, Chowdhury, Tanzina, Brok, Jesper, Ottóffy, Gábor, Xiaofei Sun, Ramírez Villar, Gema L., Sagoyan, Garik, Segers, Heidi, Doganis, Dimitrios, Serra, Annalisa, Lemelle, Lauriane, Graf, Norbert, Verschuur, Arnauld C., Tytgat, Godelieve A. M., and van den Heuvel-Eibrink, Marry M.

Subjects
RENAL cell carcinoma, PEDIATRIC oncology, KIDNEY tumors, CHILD patients, PROTEIN-tyrosine kinase inhibitors
Abstract

Introduction: Introduction: Renal cell carcinoma (RCC) is a very rare pediatric renal tumor. Robust evidence to guide treatment is lacking and knowledge on targeted therapies and immunotherapy is mainly based on adult studies. Currently, the International Society of Pediatric Oncology–Renal Tumor Study Group (SIOP-RTSG) 2016 UMBRELLA protocol recommends sunitinib for metastatic or unresectable RCC. Methods: This retrospective study describes the effects of tyrosine kinase inhibitors (TKI), anti-programmed cell death 1 (PD-(L)1) monoclonal antibodies, and immunotherapeutic regimens in advanced-stage and relapsed pediatric RCC. Results: Of the 31 identified patients (0–18 years) with histologically proven RCC, 3/31 presented with TNM stage I/II, 8/31 with TNM stage III, and 20/31 with TNM stage IV at diagnosis. The majority were diagnosed with translocation type RCC (MiT-RCC) (21/31) and the remaining patients mainly presented with papillary or clear-cell RCC. Treatment in a neoadjuvant or adjuvant setting, or upon relapse or progression, included mono- or combination therapy with a large variety of drugs, illustrating center specific choices in most patients. Sunitinib was often administered as first choice and predominantly resulted in stable disease (53%). Other frequently used drugs included axitinib, cabozantinib, sorafenib, and nivolumab; however, no treatment seemed more promising than sunitinib. Overall, 15/31 patients died of disease, 12/31 are alive with active disease, and only four patients had a complete response. The sample size and heterogeneity of this cohort only allowed descriptive statistical analysis. Conclusion: This study provides an overview of a unique series of clinical and treatment characteristics of pediatric patients with RCC treated with targeted therapies. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors

Author

van Zogchel, Lieke M. J., primary, Lak, Nathalie S. M., additional, Gelineau, Nina U., additional, Sergeeva, Irina, additional, Stelloo, Ellen, additional, Swennenhuis, Joost, additional, Feitsma, Harma, additional, van Min, Max, additional, Splinter, Erik, additional, Bleijs, Margit, additional, Groot Koerkamp, Marian, additional, Breunis, Willemijn, additional, Meister, Michael Torsten, additional, Kholossy, Waleed Hassan, additional, Holstege, Frank C. P., additional, Molenaar, Jan J., additional, de Leng, Wendy W. J., additional, Stutterheim, Janine, additional, van der Schoot, C. Ellen, additional, and Tytgat, Godelieve A. M., additional

Published
2023
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29. Cell-Free RNA from Plasma in Patients with Neuroblastoma: Exploring the Technical and Clinical Potential

Author

Lak, Nathalie S. M., primary, Seijger, Anne, additional, van Zogchel, Lieke M. J., additional, Gelineau, Nina U., additional, Javadi, Ahmad, additional, Zappeij-Kannegieter, Lily, additional, Bongiovanni, Laura, additional, Andriessen, Anneloes, additional, Stutterheim, Janine, additional, van der Schoot, C. Ellen, additional, de Bruin, Alain, additional, and Tytgat, Godelieve A. M., additional

Published
2023
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30. Humanized MISTRG as a preclinical in vivo model to study human neutrophil-mediated immune processes

Author

Martinez-Sanz, Paula, primary, Laurent, Adrien R. G., additional, Slot, Edith, additional, Hoogenboezem, Mark, additional, Bąbała, Nikolina, additional, van Bruggen, Robin, additional, Rongvaux, Anthony, additional, Flavell, Richard A., additional, Tytgat, Godelieve A. M., additional, Franke, Katka, additional, Matlung, Hanke L., additional, Kuijpers, Taco W., additional, Amsen, Derk, additional, and Karrich, Julien J., additional

Published
2023
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31. MEK inhibition causes BIM stabilization and increased sensitivity to BCL-2 family member inhibitors in RAS-MAPK-mutated neuroblastoma

Author

Eleveld, Thomas F., primary, Vernooij, Lindy, additional, Schild, Linda, additional, Koopmans, Bianca, additional, Alles, Lindy K., additional, Ebus, Marli E., additional, Dandis, Rana, additional, van Tinteren, Harm, additional, Caron, Huib N., additional, Koster, Jan, additional, van Noesel, Max M., additional, Tytgat, Godelieve A. M., additional, Eising, Selma, additional, Versteeg, Rogier, additional, Dolman, M. Emmy M., additional, and Molenaar, Jan J., additional

Published
2023
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32. Correction to:[18F]mFBG PET‑CT for detection and localisation of neuroblastoma: a prospective pilot study (European Journal of Nuclear Medicine and Molecular Imaging, (2023), 50, 4, (1146-1157), 10.1007/s00259-022-06063-6)

Author

Samim, Atia, Blom, Thomas, Poot, Alex J., Windhorst, Albert D., Fiocco, Marta, Tolboom, Nelleke, Braat, Arthur J. A. T., Viol, Sebastiaan L. Meyer, van Rooij, Rob, van Noesel, Max M., Lam, Marnix G. E. H., Tytgat, Godelieve A. M., de Keizer, Bart, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, and CCA - Imaging and biomarkers

Abstract

The article [ 18F]mFBG PET‑CT for detection and localisation of neuroblastoma: a prospective pilot study, written by Atia Samim, Thomas Blom, Alex J. Poot, Albert D. Windhorst, Marta Fiocco, Nelleke Tolboom, Arthur J. A. T. Braat, Sebastiaan L. Meyer Viol, Rob van Rooij, Max M. van Noesel, Marnix G. E. H. Lam, Godelieve A. M. Tytgat, and Bart de Keizer, was originally published Online First without Open Access. After publication in volume 50, issue 4, page 1146 - 1157 the author decided to opt for Open Choice and to make the article an Open Access publication.

Published
2023
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33. [18F]mFBG PET-CT for detection and localisation of neuroblastoma: a prospective pilot study

Author

Samim, Atia, primary, Blom, Thomas, additional, Poot, Alex J., additional, Windhorst, Albert D., additional, Fiocco, Marta, additional, Tolboom, Nelleke, additional, Braat, Arthur J. A. T., additional, Viol, Sebastiaan L. Meyer, additional, van Rooij, Rob, additional, van Noesel, Max M., additional, Lam, Marnix G. E. H., additional, Tytgat, Godelieve A. M., additional, and de Keizer, Bart, additional

Published
2022
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35. Extracellular Vesicles: A New Source of Biomarkers in Pediatric Solid Tumors? A Systematic Review

Author

Lak, Nathalie S. M., Van Der Kooi, Elvera J., Enciso-martinez, Agustin, Lozano-andrés, Estefanía, Otto, Cees, Wauben, Marca H. M., Tytgat, Godelieve A. M., Celbiologie, dB&C I&I, Celbiologie, and dB&C I&I

Subjects
Cancer Research, neuroblastoma, Oncology, osteosarcoma, pediatric oncology, rhabdomyosarcoma, solid tumors, hepatoblastoma, extracellular vesicles, desmoplastic small round cell tumor
Abstract

Virtually every cell in the body releases extracellular vesicles (EVs), the contents of which can provide a “fingerprint” of their cellular origin. EVs are present in all bodily fluids and can be obtained using minimally invasive techniques. Thus, EVs can provide a promising source of diagnostic, prognostic, and predictive biomarkers, particularly in the context of cancer. Despite advances using EVs as biomarkers in adult cancers, little is known regarding their use in pediatric cancers. In this review, we provide an overview of published clinical and in vitro studies in order to assess the potential of using EV-derived biomarkers in pediatric solid tumors. We performed a systematic literature search, which yielded studies regarding desmoplastic small round cell tumor, hepatoblastoma, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. We then determined the extent to which the in vivo findings are supported by in vitro data, and vice versa. We also critically evaluated the clinical studies using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system, and we evaluated the purification and characterization of EVs in both the in vivo and in vitro studies in accordance with MISEV guidelines, yielding EV-TRACK and PedEV scores. We found that several studies identified similar miRNAs in overlapping and distinct tumor entities, indicating the potential for EV-derived biomarkers. However, most studies regarding EV-based biomarkers in pediatric solid tumors lack a standardized system of reporting their EV purification and characterization methods, as well as validation in an independent cohort, which are needed in order to bring EV-based biomarkers to the clinic.

Published
2022

36. Optimising urinary catecholamine metabolite diagnostics for neuroblastoma.

Author

Matser, Yvette A. H., Verly, Iedan R. N., van der Ham, Maria, de Sain‐van der Velden, Monique G. M., Verhoeven‐Duif, Nanda M., Ash, Shifra, Cangemi, Giuliana, Barco, Sebastiano, Popovic, Maja Beck, van Kuilenburg, André B. P., Tytgat, Godelieve A. M., Cañete, Adela, Wieczorek, Aleksandra, Vicha, Ales, Alba, Amparo, Ryan, Anne L, Brichard, Bénédicte, Yalçın, Bilgehan, Martínez, Blanca, and Márquez, Catalina

Published
2023
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37. Refractory Stage M Ganglioneuroblastoma With Bone Metastases and a Favorable, Chronic Course of Disease: Description of a Patient Cohort

Author

Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, van Noesel, Max M, Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, and van Noesel, Max M

Abstract

Refractory stage M neuroblastoma (NB) is associated with a poor prognosis and a progressive course of disease. Here, we describe a unique group of patients with a discrepant clinical course. Seven histologically confirmed ganglioneuroblastoma (GNB) (n=6) and differentiating NB (n=1) patients were identified who were diagnosed with stage M disease based on iodine-123-metaiodobenzylguanidine avid bone metastases. Six patients started on high-risk treatment, without tumor response (stable disease). Treatment was discontinued before the start of consolidation treatment because of refractory response in all patients. Unexpectedly, after cessation of treatment no progression of disease occurred. In 2 patients, the primary tumors expanded (>25%) very slowly during 1.5 and 3 years, and remained stable thereafter. Metabolically, a slow decrease of urinary homovanillic acid and vanillylmandelic acid levels and iodine-123-metaiodobenzylguanidine avidity was observed. All patients are alive with presence of metastatic disease after a median follow-up of 17 years (range: 6.7 to 27 y). Interestingly, at diagnosis, 6 patients were asymptomatic, 6 patients had GNB morphology, and 5 patients had meningeal metastases. These are all features seen in only a small minority of stage M patients. This GNB entity illustrates the clinical heterogeneity of neuroblastic tumors and can be used to further study the developmental origin of different NB subtypes.

Published
2022

38. Extracellular Vesicles: A New Source of Biomarkers in Pediatric Solid Tumors? A Systematic Review

Author

Celbiologie, dB&C I&I, Lak, Nathalie S. M., Van Der Kooi, Elvera J., Enciso-martinez, Agustin, Lozano-andrés, Estefanía, Otto, Cees, Wauben, Marca H. M., Tytgat, Godelieve A. M., Celbiologie, dB&C I&I, Lak, Nathalie S. M., Van Der Kooi, Elvera J., Enciso-martinez, Agustin, Lozano-andrés, Estefanía, Otto, Cees, Wauben, Marca H. M., and Tytgat, Godelieve A. M.

Published
2022

39. Refractory Stage M Ganglioneuroblastoma With Bone Metastases and a Favorable, Chronic Course of Disease: Description of a Patient Cohort

Author

Afd Pharmaceutics, Pharmaceutics, Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, van Noesel, Max M, Afd Pharmaceutics, Pharmaceutics, Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, and van Noesel, Max M

Published
2022

40. Refractory Stage M Ganglioneuroblastoma With Bone Metastases and a Favorable, Chronic Course of Disease: Description of a Patient Cohort

Author

MS Radiologie, Circulatory Health, Pathologie Pathologen staf, Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, van Noesel, Max M, MS Radiologie, Circulatory Health, Pathologie Pathologen staf, Tas, Michelle L, Molenaar, Jan J, Peek, Annemarie M L, Lequin, Maarten H, Verdijk, Rob M, de Krijger, Ronald R, Tytgat, Godelieve A M, and van Noesel, Max M

Published
2022

41. Characteristics and outcome of children with renal tumors in the Netherlands: The first five-year's experience of national centralization

Author

PMC Medisch specialisten, Cancer, Genetica, MS Radiotherapie, Pathologie Pathologen staf, Genetica Klinische Genetica, Child Health, MS Radiologie, Zorgeenheid Kinderchirurgie Medisch, Speerpunt, Zorg en O&O, Roy, Prakriti, van Peer, Sophie E, de Witte, Martin M, Tytgat, Godelieve A M, Karim-Kos, Henrike E, van Grotel, Martine, van de Ven, Cees P, Mavinkurve-Groothuis, Annelies M C, Merks, Johannes H M, Kuiper, Roland P, Hol, Janna A, Janssens, Geert O R, de Krijger, Ronald R, Jongmans, Marjolijn C J, Drost, Jarno, van der Steeg, Alida F W, Littooij, Annemieke S, Wijnen, Marc H W A, van Tinteren, Harm, van den Heuvel-Eibrink, Marry M, PMC Medisch specialisten, Cancer, Genetica, MS Radiotherapie, Pathologie Pathologen staf, Genetica Klinische Genetica, Child Health, MS Radiologie, Zorgeenheid Kinderchirurgie Medisch, Speerpunt, Zorg en O&O, Roy, Prakriti, van Peer, Sophie E, de Witte, Martin M, Tytgat, Godelieve A M, Karim-Kos, Henrike E, van Grotel, Martine, van de Ven, Cees P, Mavinkurve-Groothuis, Annelies M C, Merks, Johannes H M, Kuiper, Roland P, Hol, Janna A, Janssens, Geert O R, de Krijger, Ronald R, Jongmans, Marjolijn C J, Drost, Jarno, van der Steeg, Alida F W, Littooij, Annemieke S, Wijnen, Marc H W A, van Tinteren, Harm, and van den Heuvel-Eibrink, Marry M

Published
2022

42. Thyroid function after diagnostic I-123-metaiodobenzylguanidine in children with neuroblastic tumors

Author

Endocrinologie onderzoek, Zorg en O&O, Child Health, Endocrinologie patientenzorg, Brain, Cancer, Clement, Sarah C, Tytgat, Godelieve A M, van Trotsenburg, A S Paul, Kremer, Leontien C M, van Santen, Hanneke M, Endocrinologie onderzoek, Zorg en O&O, Child Health, Endocrinologie patientenzorg, Brain, Cancer, Clement, Sarah C, Tytgat, Godelieve A M, van Trotsenburg, A S Paul, Kremer, Leontien C M, and van Santen, Hanneke M

Published
2022

44. Characteristics and Outcome of Children with Wilms Tumor Requiring Intensive Care Admission in First Line Therapy

Author

Steur, Anouk, primary, Raymakers-Janssen, Paulien A. M. A., additional, Kneyber, Martin C. J., additional, Dijkstra, Sandra, additional, van Woensel, Job B. M., additional, van Waardenburg, Dick A., additional, van de Ven, Cornelis P., additional, van der Steeg, Alida F. W., additional, Wijnen, Marc, additional, Lilien, Marc R., additional, de Krijger, Ronald R., additional, van Tinteren, Harm, additional, Littooij, Annemieke S., additional, Janssens, Geert O., additional, Peek, Annemarie M. L., additional, Tytgat, Godelieve A. M., additional, Mavinkurve-Groothuis, Annelies M., additional, van Grotel, Martine, additional, van den Heuvel-Eibrink, Marry M., additional, and Asperen, Roelie M. Wösten-van, additional

Published
2022
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45. [18F]mFBG PET-CT for detection and localisation of neuroblastoma: a prospective pilot study.

Author

Samim, Atia, Blom, Thomas, Poot, Alex J., Windhorst, Albert D., Fiocco, Marta, Tolboom, Nelleke, Braat, Arthur J. A. T., Viol, Sebastiaan L. Meyer, van Rooij, Rob, van Noesel, Max M., Lam, Marnix G. E. H., Tytgat, Godelieve A. M., and de Keizer, Bart

Subjects
NEUROBLASTOMA, NORADRENALINE, POSITRON emission tomography, SOFT tissue infections, PEDIATRIC oncology
Abstract

Purpose: Meta-[18F]fluorobenzylguanidine ([18F]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine transporter. This pilot study investigates the feasibility of [18F]mFBG PET-CT for imaging in neuroblastoma. Methods: In a prospective, single-centre study, we recruited children with neuroblastoma, referred for meta-[123I]iodobenzylguanidine ([123I]mIBG) scanning, consisting of total body planar scintigraphy in combination with single-photon emission computed tomography-CT (SPECT-CT). Within two weeks of [123I]mIBG scanning, total body PET-CTs were performed at 1 h and 2 h after injection of [18F]mFBG (2 MBq/kg). Detected tumour localisations on scan pairs were compared. Soft tissue disease was quantified by number of lesions and skeletal disease by SIOPEN score. Results: Twenty paired [123I]mIBG and [18F]mFBG scans were performed in 14 patients (median age 4.9 years, n = 13 stage 4 disease and n = 1 stage 4S). [18F]mFBG injection was well tolerated and no related adverse events occurred in any of the patients. Mean scan time for [18F]mFBG PET-CT (9.0 min, SD 1.9) was significantly shorter than for [123I]mIBG scanning (84.5 min, SD 10.5), p < 0.01. Most tumour localisations were detected on the 1 h versus 2 h post-injection [18F]mFBG PET-CT. Compared to [123I]mIBG scanning, [18F]mFBG PET-CT detected a higher, equal, and lower number of soft tissue lesions in 40%, 55%, and 5% of scan pairs, respectively, and a higher, equal, and lower SIOPEN score in 55%, 30%, and 15% of scan pairs, respectively. On average, two more soft tissue lesions and a 6-point higher SIOPEN score were detected per patient on [18F]mFBG PET-CT compared to [123I]mIBG scanning. Conclusion: Results of this study demonstrate feasibility of [18F]mFBG PET-CT for neuroblastoma imaging. More neuroblastoma localisations were detected on [18F]mFBG PET-CT compared to [123I]mIBG scanning. [18F]mFBG PET-CT shows promise for future staging and response assessment in neuroblastoma. Trial registration: Dutch Trial Register NL8152. [ABSTRACT FROM AUTHOR]

Published
2023
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46. Characteristics and outcome of children with renal tumors in the Netherlands: The first five-year’s experience of national centralization

Author

Roy, Prakriti, primary, van Peer, Sophie E., additional, de Witte, Martin M., additional, Tytgat, Godelieve A. M., additional, Karim-Kos, Henrike E., additional, van Grotel, Martine, additional, van de Ven, Cees P., additional, Mavinkurve-Groothuis, Annelies M. C., additional, Merks, Johannes H. M., additional, Kuiper, Roland P., additional, Hol, Janna A., additional, Janssens, Geert O. R., additional, de Krijger, Ronald R., additional, Jongmans, Marjolijn C. J., additional, Drost, Jarno, additional, van der Steeg, Alida F. W., additional, Littooij, Annemieke S., additional, Wijnen, Marc H. W. A., additional, van Tinteren, Harm, additional, and van den Heuvel-Eibrink, Marry M., additional

Published
2022
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48. Bilateral Renal Tumors in Children: The First 5 Years’ Experience of National Centralization in The Netherlands and a Narrative Review of the Literature

Author

van Peer, Sophie E., primary, Hol, Janna A., additional, van der Steeg, Alida F. W., additional, Grotel, Martine van, additional, Tytgat, Godelieve A. M., additional, Mavinkurve-Groothuis, Annelies M. C., additional, Janssens, Geert O. R., additional, Littooij, Annemieke S., additional, de Krijger, Ronald R., additional, Jongmans, Marjolijn C. J., additional, Lilien, Marc R., additional, Drost, Jarno, additional, Kuiper, Roland P., additional, van Tinteren, Harm, additional, Wijnen, Marc H. W. A., additional, and van den Heuvel-Eibrink, Marry M., additional

Published
2021
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50. G-CSF as a suitable alternative to GM-CSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment

Author

Martinez Sanz, Paula, van Rees, Dieke J, van Zogchel, Lieke M J, Klein, Bart, Bouti, Panagiota, Olsman, Hugo, Schornagel, Karin, Kok, Ivana, Sunak, Ali, Leeuwenburg, Kira, Timmerman, Ilse, Dierselhuis, Miranda P, Kholosy, Waleed M, Molenaar, Jan J, van Bruggen, Robin, van den Berg, Timo K, Kuijpers, Taco W, Matlung, Hanke L, Tytgat, Godelieve A M, Franke, Katka, Afd Pharmaceutics, Pharmaceutics, Afd Pharmaceutics, Pharmaceutics, AII - Cancer immunology, CCA - Cancer biology and immunology, Paediatric Infectious Diseases / Rheumatology / Immunology, AR&D - Amsterdam Reproduction & Development, and Paediatric Oncology

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, Cell Proliferation/drug effects, 0302 clinical medicine, Adjuvants, Immunologic/pharmacology, Receptors, Tumor Microenvironment, Immunology and Allergy, Cytotoxicity, Immunologic/drug effects, Trogocytosis/drug effects, immunologic, RC254-282, Antibody-dependent cell-mediated cytotoxicity, Tumor, biology, Dinutuximab, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Antineoplastic Agents, Immunological/pharmacology, Immunologic/pharmacology, Cytokine, Oncology, Integrin alpha M, Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology, 030220 oncology & carcinogenesis, Neutrophils/drug effects, Molecular Medicine, cytotoxicity, CD11b Antigen/metabolism, immunotherapy, Granulocyte Colony-Stimulating Factor/pharmacology, Immunologic/drug effects, Trogocytosis, Immunology, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Antibodies, Cell Line, 03 medical and health sciences, neuroblastoma, In vivo, Neuroblastoma, Cell Line, Tumor, medicine, CD18 Antigens/metabolism, innate, Humans, Neuroblastoma/drug therapy, Adjuvants, Pharmacology, business.industry, IgG/metabolism, Basic Tumor Immunology, Immunotherapy, Receptors, IgG/metabolism, medicine.disease, immunity, Antibodies, Monoclonal/pharmacology, Coculture Techniques, cytokines, Monoclonal/pharmacology, 030104 developmental biology, Cancer research, biology.protein, Immunological/pharmacology, business
Abstract

BackgroundCurrent immunotherapy for patients with high-risk neuroblastoma involves the therapeutic antibody dinutuximab that targets GD2, a ganglioside expressed on the majority of neuroblastoma tumors. Opsonized tumor cells are killed through antibody-dependent cellular cytotoxicity (ADCC), a process mediated by various immune cells, including neutrophils. The capacity of neutrophils to kill dinutuximab-opsonized tumor cells can be further enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been shown in the past to improve responses to anti-GD2 immunotherapy. However, access to GM-CSF (sargramostim) is limited outside of Northern America, creating a high clinical need for an alternative method to stimulate dinutuximab responsiveness in the treatment of neuroblastoma. In this in vitro study, we have investigated whether clinically well-established granulocyte colony-stimulating factor (G-CSF) can be a potentially suitable alternative for GM-CSF in the dinutuximab immunotherapy regimen of patients with neuroblastoma.MethodsWe compared the capacity of neutrophils stimulated either in vitro or in vivo with GM-CSF or G-CSF to kill dinutuximab-opsonized GD2-positive neuroblastoma cell lines and primary patient tumor material. Blocking experiments with antibodies inhibiting either respective Fc gamma receptors (FcγR) or neutrophil integrin CD11b/CD18 demonstrated the involvement of these receptors in the process of ADCC. Flow cytometry and live cell microscopy were used to quantify and visualize neutrophil-neuroblastoma interactions.ResultsWe found that G-CSF was as potent as GM-CSF in enhancing the killing capacity of neutrophils towards neuroblastoma cells. This was observed with in vitro stimulated neutrophils, and with in vivo stimulated neutrophils from both patients with neuroblastoma and healthy donors. Enhanced killing due to GM-CSF or G-CSF stimulation was consistent regardless of dinutuximab concentration, tumor-to-neutrophil ratio and concentration of the stimulating cytokine. Both GM-CSF and G-CSF stimulated neutrophils required FcγRIIa and CD11b/CD18 integrin to perform ADCC, and this was accompanied by trogocytosis of tumor material by neutrophils and tumor cell death in both stimulation conditions.ConclusionsOur preclinical data support the use of G-CSF as an alternative stimulating cytokine to GM-CSF in the treatment of high-risk neuroblastoma with dinutuximab, warranting further testing of G-CSF in a clinical setting.

Published
2021
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