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2. Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1

Author

CTI Nierkens, Cancer, Infection & Immunity, MDL onderzoek 2, CDL Nanomedicine, CTI Kuball, MS Hematologie, Regenerative Medicine and Stem Cells, CTI Research, Cornel, Annelisa M, van der Sman, Loutje, van Dinter, Jip T, Arrabito, Marta, Dunnebach, Ester, van Hoesel, Marliek, Kluiver, Thomas A, Lopes, Ana P, Dautzenberg, Noël M M, Dekker, Linde, van Rijn, Jorik M, van den Beemt, Denise A M H, Buhl, Juliane L, du Chatinier, Aimee, Barneh, Farnaz, Lu, Yuyan, Lo Nigro, Luca, Krippner-Heidenreich, Anja, Sebestyén, Zsolt, Kuball, Jurgen, Hulleman, Esther, Drost, Jarno, van Heesch, Sebastiaan, Heidenreich, Olaf T, Peng, Weng Chuan, Nierkens, Stefan, CTI Nierkens, Cancer, Infection & Immunity, MDL onderzoek 2, CDL Nanomedicine, CTI Kuball, MS Hematologie, Regenerative Medicine and Stem Cells, CTI Research, Cornel, Annelisa M, van der Sman, Loutje, van Dinter, Jip T, Arrabito, Marta, Dunnebach, Ester, van Hoesel, Marliek, Kluiver, Thomas A, Lopes, Ana P, Dautzenberg, Noël M M, Dekker, Linde, van Rijn, Jorik M, van den Beemt, Denise A M H, Buhl, Juliane L, du Chatinier, Aimee, Barneh, Farnaz, Lu, Yuyan, Lo Nigro, Luca, Krippner-Heidenreich, Anja, Sebestyén, Zsolt, Kuball, Jurgen, Hulleman, Esther, Drost, Jarno, van Heesch, Sebastiaan, Heidenreich, Olaf T, Peng, Weng Chuan, and Nierkens, Stefan

Published
2024

3. Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia

Author

van Tilburg, Cornelis M., Milde, Till, Witt, Ruth, Ecker, Jonas, Hielscher, Thomas, Seitz, Angelika, Schenk, Jens-Peter, Buhl, Juliane L., Riehl, Dennis, Frühwald, Michael C., Pekrun, Arnulf, Rossig, Claudia, Wieland, Regina, Flotho, Christian, Kordes, Uwe, Gruhn, Bernd, Simon, Thorsten, Linderkamp, Christin, Sahm, Felix, Taylor, Lenka, Freitag, Angelika, Burhenne, Jürgen, Foerster, Kathrin I., Meid, Andreas D., Pfister, Stefan M., Karapanagiotou-Schenkel, Irini, and Witt, Olaf

Published
2019
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4. Suppl. Table S2 from A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF-Driven Pediatric Low-Grade Glioma Cells

Author

Usta, Diren, primary, Sigaud, Romain, primary, Buhl, Juliane L., primary, Selt, Florian, primary, Marquardt, Viktoria, primary, Pauck, David, primary, Jansen, Jennifer, primary, Pusch, Stefan, primary, Ecker, Jonas, primary, Hielscher, Thomas, primary, Vollmer, Johanna, primary, Sommerkamp, Alexander C., primary, Rubner, Tobias, primary, Hargrave, Darren, primary, van Tilburg, Cornelis M., primary, Pfister, Stefan M., primary, Jones, David T.W., primary, Remke, Marc, primary, Brummer, Tilman, primary, Witt, Olaf, primary, and Milde, Till, primary

Published
2023
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5. Data from A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF-Driven Pediatric Low-Grade Glioma Cells

Author

Usta, Diren, primary, Sigaud, Romain, primary, Buhl, Juliane L., primary, Selt, Florian, primary, Marquardt, Viktoria, primary, Pauck, David, primary, Jansen, Jennifer, primary, Pusch, Stefan, primary, Ecker, Jonas, primary, Hielscher, Thomas, primary, Vollmer, Johanna, primary, Sommerkamp, Alexander C., primary, Rubner, Tobias, primary, Hargrave, Darren, primary, van Tilburg, Cornelis M., primary, Pfister, Stefan M., primary, Jones, David T.W., primary, Remke, Marc, primary, Brummer, Tilman, primary, Witt, Olaf, primary, and Milde, Till, primary

Published
2023
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6. Supplementary Figures S1-S5 from A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF-Driven Pediatric Low-Grade Glioma Cells

Author

Usta, Diren, primary, Sigaud, Romain, primary, Buhl, Juliane L., primary, Selt, Florian, primary, Marquardt, Viktoria, primary, Pauck, David, primary, Jansen, Jennifer, primary, Pusch, Stefan, primary, Ecker, Jonas, primary, Hielscher, Thomas, primary, Vollmer, Johanna, primary, Sommerkamp, Alexander C., primary, Rubner, Tobias, primary, Hargrave, Darren, primary, van Tilburg, Cornelis M., primary, Pfister, Stefan M., primary, Jones, David T.W., primary, Remke, Marc, primary, Brummer, Tilman, primary, Witt, Olaf, primary, and Milde, Till, primary

Published
2023
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7. Supplemental Table Legend from A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF-Driven Pediatric Low-Grade Glioma Cells

Author

Usta, Diren, primary, Sigaud, Romain, primary, Buhl, Juliane L., primary, Selt, Florian, primary, Marquardt, Viktoria, primary, Pauck, David, primary, Jansen, Jennifer, primary, Pusch, Stefan, primary, Ecker, Jonas, primary, Hielscher, Thomas, primary, Vollmer, Johanna, primary, Sommerkamp, Alexander C., primary, Rubner, Tobias, primary, Hargrave, Darren, primary, van Tilburg, Cornelis M., primary, Pfister, Stefan M., primary, Jones, David T.W., primary, Remke, Marc, primary, Brummer, Tilman, primary, Witt, Olaf, primary, and Milde, Till, primary

Published
2023
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8. Table S4 from The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma

Author

Buhl, Juliane L., primary, Selt, Florian, primary, Hielscher, Thomas, primary, Guiho, Romain, primary, Ecker, Jonas, primary, Sahm, Felix, primary, Ridinger, Johannes, primary, Riehl, Dennis, primary, Usta, Diren, primary, Ismer, Britta, primary, Sommerkamp, Alexander C., primary, Martinez-Barbera, J.P., primary, Wefers, Annika K., primary, Remke, Marc, primary, Picard, Daniel, primary, Pusch, Stefan, primary, Gronych, Jan, primary, Oehme, Ina, primary, van Tilburg, Cornelis M., primary, Kool, Marcel, primary, Kuhn, Daniela, primary, Capper, David, primary, von Deimling, Andreas, primary, Schuhmann, Martin U., primary, Herold-Mende, Christel, primary, Korshunov, Andrey, primary, Brummer, Tilman, primary, Pfister, Stefan M., primary, Jones, David T.W., primary, Witt, Olaf, primary, and Milde, Till, primary

Published
2023
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9. Supplemental Table Legend from The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma

Author

Buhl, Juliane L., primary, Selt, Florian, primary, Hielscher, Thomas, primary, Guiho, Romain, primary, Ecker, Jonas, primary, Sahm, Felix, primary, Ridinger, Johannes, primary, Riehl, Dennis, primary, Usta, Diren, primary, Ismer, Britta, primary, Sommerkamp, Alexander C., primary, Martinez-Barbera, J.P., primary, Wefers, Annika K., primary, Remke, Marc, primary, Picard, Daniel, primary, Pusch, Stefan, primary, Gronych, Jan, primary, Oehme, Ina, primary, van Tilburg, Cornelis M., primary, Kool, Marcel, primary, Kuhn, Daniela, primary, Capper, David, primary, von Deimling, Andreas, primary, Schuhmann, Martin U., primary, Herold-Mende, Christel, primary, Korshunov, Andrey, primary, Brummer, Tilman, primary, Pfister, Stefan M., primary, Jones, David T.W., primary, Witt, Olaf, primary, and Milde, Till, primary

Published
2023
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10. Figure S1, Figure S2, Figure S3, Figure S4 from The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma

Author

Buhl, Juliane L., primary, Selt, Florian, primary, Hielscher, Thomas, primary, Guiho, Romain, primary, Ecker, Jonas, primary, Sahm, Felix, primary, Ridinger, Johannes, primary, Riehl, Dennis, primary, Usta, Diren, primary, Ismer, Britta, primary, Sommerkamp, Alexander C., primary, Martinez-Barbera, J.P., primary, Wefers, Annika K., primary, Remke, Marc, primary, Picard, Daniel, primary, Pusch, Stefan, primary, Gronych, Jan, primary, Oehme, Ina, primary, van Tilburg, Cornelis M., primary, Kool, Marcel, primary, Kuhn, Daniela, primary, Capper, David, primary, von Deimling, Andreas, primary, Schuhmann, Martin U., primary, Herold-Mende, Christel, primary, Korshunov, Andrey, primary, Brummer, Tilman, primary, Pfister, Stefan M., primary, Jones, David T.W., primary, Witt, Olaf, primary, and Milde, Till, primary

Published
2023
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11. LGG-17. SYNERGISTIC ACTIVITY OF MAPK INHIBITOR CLASSES REVEALED BY A NOVEL CELL-BASED MAPK ACTIVITY PEDIATRIC LOW-GRADE GLIOMA ASSAY

Author

Usta, Diren, primary, Sigaud, Romain, additional, Buhl, Juliane L, additional, Selt, Florian, additional, Marquardt, Viktoria, additional, Pauck, David, additional, Pusch, Stefan, additional, Ecker, Jonas, additional, Hielscher, Thomas, additional, Vollmer, Johanna, additional, Sommerkamp, Alexander C, additional, Rubner, Tobias, additional, Hargrave, Darren, additional, van Tilburg, Cornelis M, additional, Pfister, Stefan M, additional, Jones, David T W, additional, Remke, Marc, additional, Brummer, Tilman, additional, Witt, Olaf, additional, and Milde, Till, additional

Published
2020
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12. Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma

Author

Ecker, Jonas, primary, Thatikonda, Venu, additional, Sigismondo, Gianluca, additional, Selt, Florian, additional, Valinciute, Gintvile, additional, Oehme, Ina, additional, Müller, Carina, additional, Buhl, Juliane L, additional, Ridinger, Johannes, additional, Usta, Diren, additional, Qin, Nan, additional, van Tilburg, Cornelis M, additional, Herold-Mende, Christel, additional, Remke, Marc, additional, Sahm, Felix, additional, Westermann, Frank, additional, Kool, Marcel, additional, Wechsler-Reya, Robert J, additional, Chavez, Lukas, additional, Krijgsveld, Jeroen, additional, Jäger, Natalie, additional, Pfister, Stefan M, additional, Witt, Olaf, additional, and Milde, Till, additional

Published
2020
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13. A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF-Driven Pediatric Low-Grade Glioma Cells

Author

Usta, Diren, primary, Sigaud, Romain, additional, Buhl, Juliane L., additional, Selt, Florian, additional, Marquardt, Viktoria, additional, Pauck, David, additional, Jansen, Jennifer, additional, Pusch, Stefan, additional, Ecker, Jonas, additional, Hielscher, Thomas, additional, Vollmer, Johanna, additional, Sommerkamp, Alexander C., additional, Rubner, Tobias, additional, Hargrave, Darren, additional, van Tilburg, Cornelis M., additional, Pfister, Stefan M., additional, Jones, David T.W., additional, Remke, Marc, additional, Brummer, Tilman, additional, Witt, Olaf, additional, and Milde, Till, additional

Published
2020
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14. The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma

Author

Buhl, Juliane L., primary, Selt, Florian, additional, Hielscher, Thomas, additional, Guiho, Romain, additional, Ecker, Jonas, additional, Sahm, Felix, additional, Ridinger, Johannes, additional, Riehl, Dennis, additional, Usta, Diren, additional, Ismer, Britta, additional, Sommerkamp, Alexander C., additional, Martinez-Barbera, J.P., additional, Wefers, Annika K., additional, Remke, Marc, additional, Picard, Daniel, additional, Pusch, Stefan, additional, Gronych, Jan, additional, Oehme, Ina, additional, van Tilburg, Cornelis M., additional, Kool, Marcel, additional, Kuhn, Daniela, additional, Capper, David, additional, von Deimling, Andreas, additional, Schuhmann, Martin U., additional, Herold-Mende, Christel, additional, Korshunov, Andrey, additional, Brummer, Tilman, additional, Pfister, Stefan M., additional, Jones, David T.W., additional, Witt, Olaf, additional, and Milde, Till, additional

Published
2019
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15. Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma.

Author

Ecker, Jonas, Thatikonda, Venu, Sigismondo, Gianluca, Selt, Florian, Valinciute, Gintvile, Oehme, Ina, Müller, Carina, Buhl, Juliane L, Ridinger, Johannes, Usta, Diren, Qin, Nan, Tilburg, Cornelis M van, Herold-Mende, Christel, Remke, Marc, Sahm, Felix, Westermann, Frank, Kool, Marcel, Wechsler-Reya, Robert J, Chavez, Lukas, and Krijgsveld, Jeroen

Published
2021
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16. LGG-11. REGULATION OF ONCOGENE-INDUCED SENESCENCE IN PILOCYTIC ASTROCYTOMA

Author

Buhl, Juliane L, primary, Selt, Florian, additional, Hielscher, Thomas, additional, Sahm, Felix, additional, Capper, David, additional, Schramm, Kathrin, additional, Ridinger, Johannes, additional, Usta, Diren, additional, Ecker, Jonas, additional, Oehme, Ina, additional, Tilburg, Cornelis M van, additional, Kool, Marcel, additional, von Deimling, Andreas, additional, Schuhmann, Martin U, additional, Korshunov, Andrey, additional, Pfister, Stefan M, additional, Brummer, Tilman, additional, Jones, David T W, additional, Witt, Olaf, additional, and Milde, Till, additional

Published
2018
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17. MBRS-12. INTERFERENCE WITH THE FUNCTION OF MYC IN GROUP 3 MEDULLOBLASTOMA

Author

Ecker, Jonas, primary, Thatikonda, Venu, additional, Oehme, Ina, additional, Valinciute, Gintvile, additional, Selt, Florian, additional, Buhl, Juliane L, additional, Usta, Diren, additional, Tilburg, Cornelis M van, additional, Herold-Mende, Christel, additional, Schnölzer, Martina, additional, Warnken, Uwe, additional, Kool, Marcel, additional, Jäger, Natalie, additional, Pfister, Stefan M, additional, Witt, Olaf, additional, and Milde, Till, additional

Published
2018
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18. REGULATION OF ONCOGENE-INDUCED SENESCENCE IN PILOCYTIC ASTROCYTOMA

Author

Buhl, Juliane L., Selt, Florian, Hielscher, Thomas, Felix Sahm, Capper, David, Schramm, Kathrin, Ridinger, Johannes, Usta, Diren, Ecker, Jonas, Oehme, Ina, Tilburg, Cornelis M., Kool, Marcel, Deimling, Andreas, Schuhmann, Martin U., Korshunov, Andrey, Pfister, Stefan M., Brummer, Tilman, Jones, David T. W., Witt, Olaf, and Milde, Till

20. Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion.

Author

De Munter S, Buhl JL, De Cock L, Van Parys A, Daneels W, Pascal E, Deseins L, Ingels J, Goetgeluk G, Jansen H, Billiet L, Pille M, Van Duyse J, Bonte S, Vandamme N, Van Dorpe J, Offner F, Leclercq G, Taghon T, Depla E, Tavernier J, Kerre T, Drost J, and Vandekerckhove B

Subjects
Humans, Animals, Mice, T-Lymphocytes immunology, T-Lymphocytes metabolism, Lymphoma, Large B-Cell, Diffuse immunology, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Large B-Cell, Diffuse genetics, Gene Knockout Techniques, Cell Line, Tumor, CRISPR-Cas Systems, CD27 Ligand, Immunotherapy, Adoptive methods, Xenograft Model Antitumor Assays, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen genetics
Abstract

CD70 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy for the treatment of both solid and liquid malignancies. However, the functionality of CD70-specific CAR T cells is modest. We optimized a CD70-specific VHH-based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo, using a diffuse large B-cell lymphoma patient-derived xenograft (PDX) model. Although the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. We determined that fratricide was not causing this loss in efficacy but rather CD70 interaction in cis with the nanoCAR-induced exhaustion. Knocking out CD70 in nanoCAR T cells using CRISPR/Cas9 resulted in dramatically enhanced functionality in the diffuse large B-cell lymphoma PDX model. Through single-cell transcriptomics, we obtained evidence that CD70 knockout CD70-specific nanoCAR T cells were protected from antigen-induced exhaustion. In addition, we demonstrated that wild-type CD70-specific nanoCAR T cells already exhibited signs of exhaustion shortly after production. Their gene signature strongly overlapped with gene signatures of exhausted CAR T cells. Conversely, the gene signature of knockout CD70-specific nanoCAR T cells overlapped with the gene signature of CAR T-cell infusion products leading to complete responses in chronic lymphatic leukemia patients. Our data show that CARs targeting endogenous T-cell antigens negatively affect CAR T-cell functionality by inducing an exhausted state, which can be overcome by knocking out the specific target., (©2024 American Association for Cancer Research.)

Published
2024
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21. Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1.

Author

Cornel AM, van der Sman L, van Dinter JT, Arrabito M, Dunnebach E, van Hoesel M, Kluiver TA, Lopes AP, Dautzenberg NMM, Dekker L, van Rijn JM, van den Beemt DAMH, Buhl JL, du Chatinier A, Barneh F, Lu Y, Lo Nigro L, Krippner-Heidenreich A, Sebestyén Z, Kuball J, Hulleman E, Drost J, van Heesch S, Heidenreich OT, Peng WC, and Nierkens S

Subjects
Humans, Child, Histocompatibility Antigens Class I, Receptors, Antigen, T-Cell, Histocompatibility Antigens Class II, Minor Histocompatibility Antigens, Leukemia, Neoplasms, Germ Cell and Embryonal, Glioma
Abstract

Human leukocyte antigen (HLA) restriction of conventional T-cell targeting introduces complexity in generating T-cell therapy strategies for patients with cancer with diverse HLA-backgrounds. A subpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant T-cells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancer-specific metabolites. It is hypothesized that the MC.7.G5 MR1T-clone has potential as a pan-cancer, pan-population T-cell immunotherapy approach. These cells are irresponsive to healthy tissue while conferring T-cell receptor(TCR) dependent, HLA-independent cytotoxicity to a wide range of adult cancers. Studies so far are limited to adult malignancies. Here, we investigated the potential of MR1-targeting cellular therapy strategies in pediatric cancer. Bulk RNA sequencing data of primary pediatric tumors were analyzed to assess MR1 expression. In vitro pediatric tumor models were subsequently screened to evaluate their susceptibility to engineered MC.7.G5 TCR-expressing T-cells. Targeting capacity was correlated with qPCR-based MR1 mRNA and protein overexpression. RNA expression of MR1 in primary pediatric tumors varied widely within and between tumor entities. Notably, embryonal tumors exhibited significantly lower MR1 expression than other pediatric tumors. In line with this, most screened embryonal tumors displayed resistance to MR1T-targeting in vitro MR1T susceptibility was observed particularly in pediatric leukemia and diffuse midline glioma models. This study demonstrates potential of MC.7.G5 MR1T-cell immunotherapy in pediatric leukemias and diffuse midline glioma, while activity against embryonal tumors was limited. The dismal prognosis associated with relapsed/refractory leukemias and high-grade brain tumors highlights the promise to improve survival rates of children with these cancers., Competing Interests: Competing interests: ZS and JK are inventors on different patents for γδ TCR sequences, recognition mechanisms and isolation strategies. JK is scientific cofounder and shareholder of Gadeta (www.gadeta.nl). The remaining authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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