47 results on '"Ton, N"'
Search Results
2. Author Correction: Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial
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Verschoor, Yara L., van de Haar, Joris, van den Berg, José G., van Sandick, Johanna W., Kodach, Liudmila L., van Dieren, Jolanda M., Balduzzi, Sara, Grootscholten, Cecile, IJsselsteijn, Marieke E., Veenhof, Alexander A. F. A., Hartemink, Koen J., Vollebergh, Marieke A., Jurdi, Adham, Sharma, Shruti, Spickard, Erik, Owers, Emilia C., Bartels-Rutten, Annemarieke, den Hartog, Peggy, de Miranda, Noel F. C. C., van Leerdam, Monique E., Haanen, John B. A. G., Schumacher, Ton N., Voest, Emile E., and Chalabi, Myriam
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- 2024
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3. An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer
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Voabil, Paula, de Bruijn, Marjolein, Roelofsen, Lisanne M., Hendriks, Sanne H., Brokamp, Simone, van den Braber, Marlous, Broeks, Annegien, Sanders, Joyce, Herzig, Petra, Zippelius, Alfred, Blank, Christian, Hartemink, Koen J., Monkhorst, Kim, Haanen, John B.A.G., Schumacher, Ton N., and Thommen, Daniela S.
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Oncology, Experimental ,Tumors -- Models -- Care and treatment -- Patient outcomes ,Organs, Culture of -- Usage ,Immune response -- Health aspects -- Research ,Immunotherapy -- Patient outcomes ,Cancer -- Research ,Biological sciences ,Health - Abstract
Inhibitors of the PD-1-PD-L1 axis have been approved as therapy for many human cancers. In spite of the evidence for their widespread clinical activity, little is known about the immunological alterations that occur in human cancer tissue after PD-1 blockade. We developed and employed a patient-derived tumor fragment platform to dissect the early immunological response of human tumor tissue to ex vivo PD-1 blockade. We observed that the capacity of immune cells to be reactivated ex vivo was predictive of clinical response, and perturbation analyses identified tumor-resident T cells as a key component of this immunological response. In addition, through combined analysis of baseline properties and immune response capacity, we identified a new subgroup of infiltrated tumors that lacks the capacity to respond to PD-1 blockade. Finally, the baseline presence of tertiary lymphoid structures and their components correlated with the capacity of cancers to undergo intratumoral immune cell reactivation. An ex vivo platform of patient-derived tumor fragments enables the assessment of intratumoral immune reactivation after PD-1 blockade that is predictive of clinical outcomes in patients with cancer., Author(s): Paula Voabil [sup.1] , Marjolein de Bruijn [sup.2] , Lisanne M. Roelofsen [sup.2] , Sanne H. Hendriks [sup.2] [sup.7] , Simone Brokamp [sup.2] , Marlous van den Braber [sup.2] [...]
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- 2021
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4. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial
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van Dijk, Nick, Gil-Jimenez, Alberto, Silina, Karina, Hendricksen, Kees, Smit, Laura A., de Feijter, Jeantine M., van Montfoort, Maurits L., van Rooijen, Charlotte, Peters, Dennis, Broeks, Annegien, van der Poel, Henk G., Bruining, Annemarie, Lubeck, Yoni, Sikorska, Karolina, Boellaard, Thierry N., Kvistborg, Pia, Vis, Daniel J., Hooijberg, Erik, Schumacher, Ton N., van den Broek, Maries, Wessels, Lodewyk F. A., Blank, Christian U., van Rhijn, Bas W., and van der Heijden, Michiel S.
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- 2020
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5. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers
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Chalabi, Myriam, Fanchi, Lorenzo F., Dijkstra, Krijn K., Van den Berg, José G., Aalbers, Arend G., Sikorska, Karolina, Lopez-Yurda, Marta, Grootscholten, Cecile, Beets, Geerard L., Snaebjornsson, Petur, Maas, Monique, Mertz, Marjolijn, Veninga, Vivien, Bounova, Gergana, Broeks, Annegien, Beets-Tan, Regina G., de Wijkerslooth, Thomas R., van Lent, Anja U., Marsman, Hendrik A., Nuijten, Elvira, Kok, Niels F., Kuiper, Maria, Verbeek, Wieke H., Kok, Marleen, Van Leerdam, Monique E., Schumacher, Ton N., Voest, Emile E., and Haanen, John B.
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- 2020
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6. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial
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Voorwerk, Leonie, Slagter, Maarten, Horlings, Hugo M., Sikorska, Karolina, van de Vijver, Koen K., de Maaker, Michiel, Nederlof, Iris, Kluin, Roelof J. C., Warren, Sarah, Ong, SuFey, Wiersma, Terry G., Russell, Nicola S., Lalezari, Ferry, Schouten, Philip C., Bakker, Noor A. M., Ketelaars, Steven L. C., Peters, Dennis, Lange, Charlotte A. H., van Werkhoven, Erik, van Tinteren, Harm, Mandjes, Ingrid A. M., Kemper, Inge, Onderwater, Suzanne, Chalabi, Myriam, Wilgenhof, Sofie, Haanen, John B. A. G., Salgado, Roberto, de Visser, Karin E., Sonke, Gabe S., Wessels, Lodewyk F. A., Linn, Sabine C., Schumacher, Ton N., Blank, Christian U., and Kok, Marleen
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- 2019
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7. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers
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Scheper, Wouter, Kelderman, Sander, Fanchi, Lorenzo F., Linnemann, Carsten, Bendle, Gavin, de Rooij, Marije A. J., Hirt, Christian, Mezzadra, Riccardo, Slagter, Maarten, Dijkstra, Krijn, Kluin, Roelof J. C., Snaebjornsson, Petur, Milne, Katy, Nelson, Brad H., Zijlmans, Henry, Kenter, Gemma, Voest, Emile E., Haanen, John B. A. G., and Schumacher, Ton N.
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- 2019
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8. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma
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Blank, Christian U., Rozeman, Elisa A., Fanchi, Lorenzo F., Sikorska, Karolina, van de Wiel, Bart, Kvistborg, Pia, Krijgsman, Oscar, van den Braber, Marlous, Philips, Daisy, Broeks, Annegien, van Thienen, Johannes V., Mallo, Henk A., Adriaansz, Sandra, ter Meulen, Sylvia, Pronk, Loes M., Grijpink-Ongering, Lindsay G., Bruining, Annemarie, Gittelman, Rachel M., Warren, Sarah, van Tinteren, Harm, Peeper, Daniel S., Haanen, John B. A. G., van Akkooi, Alexander C. J., and Schumacher, Ton N.
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- 2018
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9. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade
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Thommen, Daniela S., Koelzer, Viktor H., Herzig, Petra, Roller, Andreas, Trefny, Marcel, Dimeloe, Sarah, Kiialainen, Anna, Hanhart, Jonathan, Schill, Catherine, Hess, Christoph, Savic Prince, Spasenija, Wiese, Mark, Lardinois, Didier, Ho, Ping-Chih, Klein, Christian, Karanikas, Vaios, Mertz, Kirsten D., Schumacher, Ton N., and Zippelius, Alfred
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- 2018
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10. Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial
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Nederlof, Iris, Isaeva, Olga I., de Graaf, Manon, Gielen, Robbert C. A. M., Bakker, Noor A. M., Rolfes, Adrianne L., Garner, Hannah, Boeckx, Bram, Traets, Joleen J. H., Mandjes, Ingrid A. M., de Maaker, Michiel, van Brussel, Thomas, Chelushkin, Maksim, Champanhet, Elisa, Lopez-Yurda, Marta, van de Vijver, Koen, van den Berg, José G., Hofland, Ingrid, Klioueva, Natasja, Mann, Ritse M., Loo, Claudette E., van Duijnhoven, Frederieke H., Skinner, Victoria, Luykx, Sylvia, Kerver, Emile, Kalashnikova, Ekaterina, van Dongen, Marloes G. J., Sonke, Gabe S., Linn, Sabine C., Blank, Christian U., de Visser, Karin E., Salgado, Roberto, Wessels, Lodewyk F. A., Drukker, Caroline A., Schumacher, Ton N., Horlings, Hugo M., Lambrechts, Diether, and Kok, Marleen
- Abstract
Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II–III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8+T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8+T cells, follicular helper T cells and shorter distances between tumor and CD8+T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon’s two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890.
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- 2024
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11. An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer
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Simone Brokamp, Annegien Broeks, Christian U. Blank, Petra Herzig, Marlous van den Braber, Daniela S. Thommen, Alfred Zippelius, Marjolein de Bruijn, Joyce Sanders, Ton N. Schumacher, Lisanne M. Roelofsen, Koen J. Hartemink, John B. A. G. Haanen, Kim Monkhorst, Paula Voabil, and Sanne H. Hendriks
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business.industry ,medicine.medical_treatment ,Cell ,Cancer ,General Medicine ,Immunotherapy ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Blockade ,medicine.anatomical_structure ,Immune system ,Cell culture ,medicine ,Cancer research ,Pd 1 blockade ,business ,Ex vivo - Abstract
Inhibitors of the PD-1–PD-L1 axis have been approved as therapy for many human cancers. In spite of the evidence for their widespread clinical activity, little is known about the immunological alterations that occur in human cancer tissue after PD-1 blockade. We developed and employed a patient-derived tumor fragment platform to dissect the early immunological response of human tumor tissue to ex vivo PD-1 blockade. We observed that the capacity of immune cells to be reactivated ex vivo was predictive of clinical response, and perturbation analyses identified tumor-resident T cells as a key component of this immunological response. In addition, through combined analysis of baseline properties and immune response capacity, we identified a new subgroup of infiltrated tumors that lacks the capacity to respond to PD-1 blockade. Finally, the baseline presence of tertiary lymphoid structures and their components correlated with the capacity of cancers to undergo intratumoral immune cell reactivation. An ex vivo platform of patient-derived tumor fragments enables the assessment of intratumoral immune reactivation after PD-1 blockade that is predictive of clinical outcomes in patients with cancer.
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- 2021
12. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma
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A.C.J. van Akkooi, Judith M. Versluis, Christian U. Blank, Charlotte L. Zuur, Elisa A. Rozeman, Willem M.C. Klop, Esmée P. Hoefsmit, Lindsay G Grijpink-Ongering, María Jesús González González, Sandra Adriaansz, Robyn P. M. Saw, Sydney Ch'ng, Sten Cornelissen, J Stretch, Annegien Broeks, Ton N. Schumacher, A A Torres Acosta, Hanna Eriksson, Ron M. Kerkhoven, B.A. van de Wiel, Petros Dimitriadis, Richard A. Scolyer, Oscar Krijgsman, Daniel S. Peeper, J.B.A.G. Haanen, Omgo E. Nieweg, Karolina Sikorska, Kerwin F. Shannon, Georgina V. Long, W.J. van Houdt, A.M. Menzies, H. Mallo, Irene L.M. Reijers, and Andrew J. Spillane
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Melanoma ,Phases of clinical research ,Ipilimumab ,General Medicine ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,law.invention ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Randomized controlled trial ,law ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adjuvant therapy ,Biomarker (medicine) ,Nivolumab ,business ,medicine.drug - Abstract
Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P
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- 2021
13. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial
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Maurits L. van Montfoort, Daniel J. Vis, Kees Hendricksen, Nick van Dijk, Laura A. Smit, Michiel S. van der Heijden, Henk G. van der Poel, Maries van den Broek, Christian U. Blank, Annemarie Bruining, Yoni Lubeck, Lodewyk F. A. Wessels, Dennis Peters, Pia Kvistborg, Karina Silina, Ton N. Schumacher, Charlotte van Rooijen, Karolina Sikorska, Erik Hooijberg, Annegien Broeks, Bas W.G. van Rhijn, Alberto Gil-Jimenez, Jeantine M de Feijter, Thierry N. Boellaard, University of Zurich, van der Heijden, Michiel S, and Graduate School
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,610 Medicine & health ,Ipilimumab ,10263 Institute of Experimental Immunology ,Gastroenterology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,1300 General Biochemistry, Genetics and Molecular Biology ,Neoplasms ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Humans ,Medicine ,CTLA-4 Antigen ,Stage (cooking) ,Adverse effect ,Aged ,Neoplasm Staging ,business.industry ,Antibodies, Monoclonal ,General Medicine ,Immunotherapy ,Middle Aged ,Clinical trial ,Nivolumab ,030104 developmental biology ,030220 oncology & carcinogenesis ,Monoclonal ,570 Life sciences ,biology ,Female ,Urothelium ,business ,medicine.drug - Abstract
Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma1 and colorectal cancer2. In NABUCCO (ClinicalTrials.gov: NCT03387761 ), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two doses of nivolumab, followed by resection. The primary endpoint was feasibility to resect within 12 weeks from treatment start. All patients were evaluable for the study endpoints and underwent resection, 23 (96%) within 12 weeks. Grade 3-4 immune-related adverse events occurred in 55% of patients and in 41% of patients when excluding clinically insignificant laboratory abnormalities. Eleven patients (46%) had a pathological complete response (pCR), meeting the secondary efficacy endpoint. Fourteen patients (58%) had no remaining invasive disease (pCR or pTisN0/pTaN0). In contrast to studies with anti-PD1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab was independent of baseline CD8+ presence or T-effector signatures. Induction of tertiary lymphoid structures upon treatment was observed in responding patients. Our data indicate that combined CTLA-4 plus PD-1 blockade might provide an effective preoperative treatment strategy in locoregionally advanced UC, irrespective of pre-existing CD8+ T cell activity.
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- 2020
14. Publisher Correction: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial
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Voorwerk, Leonie, Slagter, Maarten, Horlings, Hugo M., Sikorska, Karolina, van de Vijver, Koen K., de Maaker, Michiel, Nederlof, Iris, Kluin, Roelof J. C., Warren, Sarah, Ong, SuFey, Wiersma, Terry G., Russell, Nicola S., Lalezari, Ferry, Schouten, Philip C., Bakker, Noor A. M., Ketelaars, Steven L. C., Peters, Dennis, Lange, Charlotte A. H., van Werkhoven, Erik, van Tinteren, Harm, Mandjes, Ingrid A. M., Kemper, Inge, Onderwater, Suzanne, Chalabi, Myriam, Wilgenhof, Sofie, Haanen, John B. A. G., Salgado, Roberto, de Visser, Karin E., Sonke, Gabe S., Wessels, Lodewyk F. A., Linn, Sabine C., Schumacher, Ton N., Blank, Christian U., and Kok, Marleen
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- 2019
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15. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial
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Gabe S. Sonke, Ferry Lalezari, Leonie Voorwerk, John B. A. G. Haanen, SuFey Ong, T. Wiersma, Noor A. M. Bakker, Philip C. Schouten, Ton N. Schumacher, Harm van Tinteren, Inge Kemper, Karin E. de Visser, Nicola S. Russell, Hugo M. Horlings, Karolina Sikorska, Maarten Slagter, Marleen Kok, Sarah Warren, I.A.M. Mandjes, Erik van Werkhoven, Myriam Chalabi, Michiel de Maaker, Dennis Peters, Sofie Wilgenhof, Iris Nederlof, Sabine C. Linn, Suzanne Onderwater, Charlotte A.H. Lange, Roelof J.C. Kluin, Roberto Salgado, Koen Van de Vijver, Lodewyk F. A. Wessels, Steven L. C. Ketelaars, Christian U. Blank, AII - Cancer immunology, CCA - Imaging and biomarkers, CCA - Cancer biology and immunology, Graduate School, APH - Methodology, and APH - Personalized Medicine
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0301 basic medicine ,Cisplatin ,Tumor microenvironment ,Chemotherapy ,business.industry ,medicine.medical_treatment ,General Medicine ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Blockade ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Doxorubicin ,Nivolumab ,business ,Triple-negative breast cancer ,medicine.drug - Abstract
The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer ( TNBC ) is low1–5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6–13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1–PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK–STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types. A pick-the-winner clinical trial design in patients with metastatic triple-negative breast cancer shows that immune induction with doxorubicin or cisplatin may improve clinical responses to PD-1 blockade and induce a more favorable tumor microenvironment.
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- 2019
16. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers
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Gavin M. Bendle, Roelof J.C. Kluin, Wouter Scheper, Petur Snaebjornsson, Carsten Linnemann, Gemma G. Kenter, Marije A. J. de Rooij, John B. A. G. Haanen, Riccardo Mezzadra, Christian Hirt, Ton N. Schumacher, Emile E. Voest, Sander Kelderman, Krijn K. Dijkstra, Brad H. Nelson, Maarten Slagter, Lorenzo F. Fanchi, Katy Milne, Henry Zijlmans, Obstetrics and Gynaecology, AII - Cancer immunology, and CCA - Cancer biology and immunology
- Subjects
0301 basic medicine ,T cell ,Receptors, Antigen, T-Cell ,Biology ,CD8-Positive T-Lymphocytes ,Jurkat cells ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Jurkat Cells ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,Antigen ,Neoplasms ,medicine ,Humans ,Receptor ,T-cell receptor ,Reproducibility of Results ,General Medicine ,Acquired immune system ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,030220 oncology & carcinogenesis ,Cancer research ,Infiltration (medical) ,CD8 - Abstract
Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites1. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer—two tumor types for which T cell infiltrates form a positive prognostic marker2,3. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire. Intratumoral T cells that are capable of recognizing adjacent tumor tissue antigens can be exceedingly rare.
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- 2019
17. An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer
- Author
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Paula, Voabil, Marjolein, de Bruijn, Lisanne M, Roelofsen, Sanne H, Hendriks, Simone, Brokamp, Marlous, van den Braber, Annegien, Broeks, Joyce, Sanders, Petra, Herzig, Alfred, Zippelius, Christian U, Blank, Koen J, Hartemink, Kim, Monkhorst, John B A G, Haanen, Ton N, Schumacher, and Daniela S, Thommen
- Subjects
Antineoplastic Agents, Immunological ,Lymphocytes, Tumor-Infiltrating ,Cell Line, Tumor ,Neoplasms ,Programmed Cell Death 1 Receptor ,Tumor Microenvironment ,Cytokines ,Humans ,Cell Differentiation ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Immune Checkpoint Inhibitors ,B7-H1 Antigen - Abstract
Inhibitors of the PD-1-PD-L1 axis have been approved as therapy for many human cancers. In spite of the evidence for their widespread clinical activity, little is known about the immunological alterations that occur in human cancer tissue after PD-1 blockade. We developed and employed a patient-derived tumor fragment platform to dissect the early immunological response of human tumor tissue to ex vivo PD-1 blockade. We observed that the capacity of immune cells to be reactivated ex vivo was predictive of clinical response, and perturbation analyses identified tumor-resident T cells as a key component of this immunological response. In addition, through combined analysis of baseline properties and immune response capacity, we identified a new subgroup of infiltrated tumors that lacks the capacity to respond to PD-1 blockade. Finally, the baseline presence of tertiary lymphoid structures and their components correlated with the capacity of cancers to undergo intratumoral immune cell reactivation.
- Published
- 2020
18. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma
- Author
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Lindsay G Grijpink-Ongering, Sandra Adriaansz, Pia Kvistborg, Christian U. Blank, John B. A. G. Haanen, Annemarie Bruining, Bart A. van de Wiel, Karolina Sikorska, Daisy Philips, Lorenzo F. Fanchi, Sarah Warren, Ton N. Schumacher, Oscar Krijgsman, Daniel S. Peeper, Annegien Broeks, Harm van Tinteren, Elisa A. Rozeman, H. Mallo, Marlous van den Braber, Loes M. Pronk, Sylvia ter Meulen, Alexander C.J. van Akkooi, Johannes V. Van Thienen, and Rachel M. Gittelman
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Melanoma ,Ipilimumab ,General Medicine ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Regimen ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,Nivolumab ,business ,Adverse effect ,Adjuvant ,Neoadjuvant therapy ,medicine.drug - Abstract
Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients1,2. In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy3. Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy4. To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg−1 and nivolumab 1 mg kg−1, as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm). Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6 months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity.
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- 2018
19. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small cell lung cancer treated with PD-1 blockade
- Author
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Viktor H. Koelzer, Didier Lardinois, Kirsten D. Mertz, Spasenija Savic Prince, Ping-Chih Ho, Jonathan C Hanhart, Daniela S. Thommen, Alfred Zippelius, Catherine Schill, Marcel P. Trefny, Vaios Karanikas, Sarah Dimeloe, Ton N. Schumacher, Mark Wiese, Andreas Roller, Petra Herzig, Christoph Hess, Christian Klein, Anna Kiialainen, University of Zurich, and Thommen, Daniela S
- Subjects
0301 basic medicine ,Lung Neoplasms ,Transcription, Genetic ,medicine.medical_treatment ,T cell ,Programmed Cell Death 1 Receptor ,610 Medicine & health ,Biology ,CD8-Positive T-Lymphocytes ,NSCLC ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,1300 General Biochemistry, Genetics and Molecular Biology ,T-Lymphocyte Subsets ,10049 Institute of Pathology and Molecular Pathology ,Carcinoma, Non-Small-Cell Lung ,medicine ,Cytotoxic T cell ,Humans ,Lung cancer ,T cell exhaustion ,chemokine ,General Medicine ,T lymphocyte ,Immunotherapy ,CXCL13 ,immune checkpoint blockade ,medicine.disease ,Lipid Metabolism ,Chemokine CXCL13 ,3. Good health ,Mitochondria ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Glucose ,Phenotype ,Virus Diseases ,030220 oncology & carcinogenesis ,IL-10 ,Chronic Disease ,Cancer research ,CD8-Positive T-Lymphocytes/immunology ,CD8-Positive T-Lymphocytes/ultrastructure ,Carcinoma, Non-Small-Cell Lung/genetics ,Carcinoma, Non-Small-Cell Lung/immunology ,Chemokine CXCL13/metabolism ,Glucose/metabolism ,Lung Neoplasms/genetics ,Lung Neoplasms/immunology ,Lymphocytes, Tumor-Infiltrating/immunology ,Mitochondria/metabolism ,Mitochondria/ultrastructure ,Programmed Cell Death 1 Receptor/metabolism ,T-Lymphocyte Subsets/immunology ,Virus Diseases/immunology ,CD8 - Abstract
Evidence from mouse chronic viral infection models suggests that CD8 + T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8 + T lymphocyte populations with high (PD-1 T ), intermediate (PD-1 N ) and no PD-1 expression (PD-1 - ) from non-small-cell lung cancer patients. PD-1 T T cells showed a markedly different transcriptional and metabolic profile from PD-1 N and PD-1 - lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1 T lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1 T cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.
- Published
- 2018
20. A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression
- Author
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Bins, Adriaan D, Jorritsma, Annelies, Wolkers, Monika C, Hung, Chien-Fu, Wu, T-C, Schumacher, Ton N M, and Haanen, John B A G
- Published
- 2005
- Full Text
- View/download PDF
21. Design and use of conditional MHC class I ligands
- Author
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Toebes, Mireille, Coccoris, Miriam, Bins, Adriaan, Rodenko, Boris, Gomez, Raquel, Nieuwkoop, Nella J, van de Kasteele, Willeke, Rimmelzwaan, Guus F, Haanen, John B A G, Ovaa, Huib, and Schumacher, Ton N M
- Abstract
Major histocompatibility complex (MHC) class I molecules associate with a variety of peptide ligands during biosynthesis and present these ligands on the cell surface for recognition by cytotoxic T cells. We have designed conditional MHC ligands that form stable complexes with MHC molecules but degrade on command, by exposure to a defined photostimulus. 'Empty MHC molecules' generated in this manner can be loaded with arrays of peptide ligands to determine MHC binding properties and to monitor antigen-specific T-cell responses in a high-throughput manner. We document the value of this approach by identifying cytotoxic T-cell epitopes within the H5N1 influenza A/Vietnam/1194/04 genome., Author(s): Mireille Toebes [1]; Miriam Coccoris [1, 4]; Adriaan Bins [1, 4]; Boris Rodenko [2]; Raquel Gomez [1]; Nella J Nieuwkoop [3]; Willeke van de Kasteele [1]; Guus F Rimmelzwaan [...]
- Published
- 2006
- Full Text
- View/download PDF
22. Vaccine leads to memory loss
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Haanen, John B A G and Schumacher, Ton N M
- Published
- 2007
- Full Text
- View/download PDF
23. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers
- Author
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Emile E. Voest, Elvira Nuijten, Monique E. van Leerdam, Arend G. J. Aalbers, Annegien Broeks, José G van den Berg, Niels F. M. Kok, Marleen Kok, Wieke H M Verbeek, Petur Snaebjornsson, Myriam Chalabi, Lorenzo F. Fanchi, Ton N. Schumacher, Gergana Bounova, Maria Kuiper, Krijn K. Dijkstra, Monique Maas, Geerard L. Beets, Anja U. van Lent, John B. A. G. Haanen, Vivien Veninga, Marta Lopez-Yurda, Regina G. H. Beets-Tan, Thomas R de Wijkerslooth, Cecile Grootscholten, Hendrik A Marsman, Karolina Sikorska, Marjolijn Mertz, Faculteit FHML Centraal, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and Surgery
- Subjects
0301 basic medicine ,Oncology ,Male ,Colorectal cancer ,medicine.medical_treatment ,THERAPY ,DNA Mismatch Repair ,COLORECTAL-CANCER ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Clinical endpoint ,Treatment Failure ,Stage (cooking) ,Cells, Cultured ,Digestive System Surgical Procedures ,Aged, 80 and over ,EVASION ,General Medicine ,Middle Aged ,TUMORS ,Combined Modality Therapy ,Neoadjuvant Therapy ,Nivolumab ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,SURVIVAL ,Female ,Immunotherapy ,medicine.drug ,Adult ,medicine.medical_specialty ,Ipilimumab ,Adenocarcinoma ,General Biochemistry, Genetics and Molecular Biology ,Drug Administration Schedule ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Pathological ,Aged ,Neoplasm Staging ,business.industry ,medicine.disease ,PD-1 BLOCKADE ,030104 developmental biology ,CELLS ,Celecoxib ,Feasibility Studies ,business ,GENERATION - Abstract
PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data. Results from the NICHE study show remarkable pathological responses to neoadjuvant combination immunotherapy in patients with early-stage colon cancer and uncover potential biomarkers of response.
- Published
- 2019
24. Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy
- Author
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Logtenberg, Meike E. W., primary, Jansen, J. H. Marco, additional, Raaben, Matthijs, additional, Toebes, Mireille, additional, Franke, Katka, additional, Brandsma, Arianne M., additional, Matlung, Hanke L., additional, Fauster, Astrid, additional, Gomez-Eerland, Raquel, additional, Bakker, Noor A. M., additional, van der Schot, Simone, additional, Marijt, Koen A., additional, Verdoes, Martijn, additional, Haanen, John B. A. G., additional, van den Berg, Joost H., additional, Neefjes, Jacques, additional, van den Berg, Timo K., additional, Brummelkamp, Thijn R., additional, Leusen, Jeanette H. W., additional, Scheeren, Ferenc A., additional, and Schumacher, Ton N., additional
- Published
- 2019
- Full Text
- View/download PDF
25. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers
- Author
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Scheper, Wouter, primary, Kelderman, Sander, additional, Fanchi, Lorenzo F., additional, Linnemann, Carsten, additional, Bendle, Gavin, additional, de Rooij, Marije A. J., additional, Hirt, Christian, additional, Mezzadra, Riccardo, additional, Slagter, Maarten, additional, Dijkstra, Krijn, additional, Kluin, Roelof J. C., additional, Snaebjornsson, Petur, additional, Milne, Katy, additional, Nelson, Brad H., additional, Zijlmans, Henry, additional, Kenter, Gemma, additional, Voest, Emile E., additional, Haanen, John B. A. G., additional, and Schumacher, Ton N., additional
- Published
- 2018
- Full Text
- View/download PDF
26. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma
- Author
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Dris El Atmioui, Remko Schotte, Els M. E. Verdegaal, John B. A. G. Haanen, Laura Bies, Ton N. Schumacher, Sam Behjati, Hergen Spits, Michael R. Stratton, Marten Visser, Carsten Linnemann, Arno Velds, Jorg J A Calis, Marit M. van Buuren, Sjoerd H. van der Burg, Henk Hilkmann, AII - Amsterdam institute for Infection and Immunity, Cell Biology and Histology, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
- Subjects
CD4-Positive T-Lymphocytes ,medicine.medical_treatment ,bcl-X Protein ,Epitopes, T-Lymphocyte ,CD8-Positive T-Lymphocytes ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Antigen ,Cancer immunotherapy ,Antigens, Neoplasm ,Cell Line, Tumor ,medicine ,Humans ,Melanoma ,Antigen Presentation ,Mutation ,Cancer ,General Medicine ,Immunotherapy ,medicine.disease ,DNA-Binding Proteins ,Immunology ,Proto-Oncogene Proteins c-bcl-6 ,CD8 - Abstract
Tumor-specific neo-antigens that arise as a consequence of mutations(1,2) are thought to be important for the therapeutic efficacy of cancer immunotherapies(3-5). Accumulating evidence suggests that neo-antigens may be commonly recognized by intratumoral CD8(+) T cells(3-7), but it is unclear whether neoantigen-specific CD4(+) T cells also frequently reside within human tumors. In view of the accepted role of tumor-specific CD4(+) T-cell responses in tumor control(8-10), we addressed whether neo-antigen-specific CD4(+) T-cell reactivity is a common property in human melanoma
- Published
- 2014
27. A liquid biopsy for cancer immunotherapy
- Author
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Schumacher, Ton N. and Scheper, Wouter
- Subjects
Gene mutations -- Health aspects ,Biopsy -- Methods ,Immunotherapy -- Innovations ,Cancer -- Care and treatment ,Biological sciences ,Health - Abstract
Human T cells that target tumor-specific mutations are attractive for cancer immunotherapy, but obtaining these T cells is challenging. A new study shows that tumor mutation-specific T cells can be [...]
- Published
- 2016
28. Publisher Correction: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial
- Author
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Marleen Kok, Michiel de Maaker, Christian U. Blank, Iris Nederlof, SuFey Ong, Koen Van de Vijver, Philip C. Schouten, Sofie Wilgenhof, Karin E. de Visser, John B. A. G. Haanen, Harm van Tinteren, Hugo M. Horlings, Ferry Lalezari, Gabe S. Sonke, Erik van Werkhoven, Inge Kemper, Suzanne Onderwater, T. Wiersma, I.A.M. Mandjes, Maarten Slagter, Roberto Salgado, Sarah Warren, Charlotte A.H. Lange, Ton N. Schumacher, Roelof J.C. Kluin, Leonie Voorwerk, Nicola S. Russell, Myriam Chalabi, Noor A. M. Bakker, Karolina Sikorska, Sabine C. Linn, Lodewyk F. A. Wessels, Steven L. C. Ketelaars, and Dennis Peters
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,General Medicine ,General Biochemistry, Genetics and Molecular Biology ,Tonic (physiology) ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Text mining ,Immune system ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Pd 1 blockade ,Tumor necrosis factor alpha ,business ,Triple-negative breast cancer ,Transforming growth factor - Abstract
In the version of this article originally published, there was an error in Fig. 3j. A label on the heatmap read "TGF-α signaling via NF-κB". It should have read "TNF-α signaling via NF-κB". The error has been corrected in the HTML and PDF versions of this article.
- Published
- 2019
29. Corrigendum: High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4
- Author
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Carsten, Linnemann, Marit M, van Buuren, Laura, Bies, Els M E, Verdegaal, Remko, Schotte, Jorg J A, Calis, Sam, Behjati, Arno, Velds, Henk, Hilkmann, Dris, El Atmioui, Marten, Visser, Michael R, Stratton, John B A G, Haanen, Hergen, Spits, Sjoerd H, van der Burg, and Ton N M, Schumacher
- Published
- 2016
30. Design and use of conditional MHC class I ligands
- Author
-
Huib Ovaa, Boris Rodenko, Ton N. Schumacher, Miriam Coccoris, Adriaan Bins, Nella J. Nieuwkoop, Raquel Gomez, Mireille Toebes, John B. A. G. Haanen, Guus F. Rimmelzwaan, Willeke van de Kasteele, Other departments, Medical Oncology, and Virology
- Subjects
Models, Molecular ,Spectrometry, Mass, Electrospray Ionization ,CD74 ,Photochemistry ,Ultraviolet Rays ,Mice, Transgenic ,In Vitro Techniques ,Ligands ,Major histocompatibility complex ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Mice ,HLA-A2 Antigen ,MHC class I ,Animals ,Humans ,Cytotoxic T cell ,Amino Acid Sequence ,Genetics ,Influenza A Virus, H5N1 Subtype ,Molecular Structure ,biology ,Immunodominant Epitopes ,Histocompatibility Antigens Class I ,General Medicine ,MHC multimer ,MHC restriction ,Cell biology ,Mice, Inbred C57BL ,Drug Design ,Multiprotein Complexes ,biology.protein ,Oligopeptides ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Major histocompatibility complex (MHC) class I molecules associate with a variety of peptide ligands during biosynthesis and present these ligands on the cell surface for recognition by cytotoxic T cells. We have designed conditional MHC ligands that form stable complexes with MHC molecules but degrade on command, by exposure to a defined photostimulus. 'Empty MHC molecules' generated in this manner can be loaded with arrays of peptide ligands to determine MHC binding properties and to monitor antigen-specific T-cell responses in a high-throughput manner. We document the value of this approach by identifying cytotoxic T-cell epitopes within the H5N1 influenza A/Vietnam/1194/04 genome.
- Published
- 2006
31. A liquid biopsy for cancer immunotherapy
- Author
-
Wouter Scheper and Ton N. Schumacher
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Adoptive cell transfer ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Melanoma ,General Medicine ,Immunotherapy ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Peripheral blood ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cancer immunotherapy ,030220 oncology & carcinogenesis ,Internal medicine ,Biopsy ,Medicine ,Liquid biopsy ,business - Abstract
Human T cells that target tumor-specific mutations are attractive for cancer immunotherapy, but obtaining these T cells is challenging. A new study shows that tumor mutation–specific T cells can be isolated from the peripheral blood of patients with melanoma.
- Published
- 2016
32. Corrigendum: High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma
- Author
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Linnemann, Carsten, van Buuren, Marit M, Bies, Laura, Verdegaal, Els M E, Schotte, Remko, Calis, Jorg J A, Behjati, Sam, Velds, Arno, Hilkmann, Henk, el Atmioui, Dris, Visser, Marten, Stratton, Michael R, Haanen, John B A G, Spits, Hergen, van der Burg, Sjoerd H, and Schumacher, Ton N M
- Subjects
Biological sciences ,Health - Abstract
Author(s): Carsten Linnemann; Marit M van Buuren; Laura Bies; Els M E Verdegaal; Remko Schotte; Jorg J A Calis; Sam Behjati; Arno Velds; Henk Hilkmann; Dris el Atmioui; Marten Visser; [...]
- Published
- 2016
- Full Text
- View/download PDF
33. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy
- Author
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Rienk Offringa, Cornelis J. M. Melief, Ton N. Schumacher, den Boer At, van der Voort Ei, Stephen P. Schoenberger, Linda Diehl, and René E. M. Toes
- Subjects
CD40 Ligand ,Priming (immunology) ,chemical and pharmacologic phenomena ,Lymphocyte Activation ,Cancer Vaccines ,General Biochemistry, Genetics and Molecular Biology ,Epitopes ,Mice ,Immunity ,Immune Tolerance ,Animals ,Cytotoxic T cell ,CD40 Antigens ,Mice, Knockout ,B-Lymphocytes ,Membrane Glycoproteins ,CD40 ,biology ,Chemistry ,hemic and immune systems ,Neoplasms, Experimental ,T-Lymphocytes, Helper-Inducer ,General Medicine ,Peptide Fragments ,Mice, Inbred C57BL ,CTL ,Cell Transformation, Neoplastic ,Immunology ,Peptide vaccine ,biology.protein ,Adenovirus E1A Proteins ,Antibody ,Spleen ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
The outcome of antigen recognition by naive CD8+ cytotoxic T lymphocytes (CTLs) in the periphery is orchestrated by CD4+ T-helper cells, and can either lead to priming or tolerization. The presence of T-helper cells favors the induction of CTL immunity, whereas the absence of T-helper cells can result in CTL tolerance. The action of T helper cells in CTL priming is mediated by CD40-CD40 ligand interactions. We demonstrate here that triggering of CD40 in vivo can considerably enhance the efficacy of peptide-based anti-tumor vaccines. The combination of a tolerogenic peptide vaccine containing a minimal essential CTL epitope with an activating antibody against CD40 converts tolerization into strong CTL priming. Moreover, CD40 ligation can provide an already protective tumor-specific peptide vaccine with the capacity to induce therapeutic CTL immunity in tumor-bearing mice. These findings indicate that the CD40-CD40 ligand pair can act as a 'switch', determining whether naive peripheral CTLs are primed or tolerized, and support the clinical use of CD40-stimulating agents as components of anti-cancer vaccines.
- Published
- 1999
34. Erratum: Corrigendum: High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma
- Author
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Linnemann, Carsten, primary, van Buuren, Marit M, additional, Bies, Laura, additional, Verdegaal, Els M E, additional, Schotte, Remko, additional, Calis, Jorg J A, additional, Behjati, Sam, additional, Velds, Arno, additional, Hilkmann, Henk, additional, el Atmioui, Dris, additional, Visser, Marten, additional, Stratton, Michael R, additional, Haanen, John B A G, additional, Spits, Hergen, additional, van der Burg, Sjoerd H, additional, and Schumacher, Ton N M, additional
- Published
- 2016
- Full Text
- View/download PDF
35. Vaccine leads to memory loss
- Author
-
Ton N. Schumacher and John B. A. G. Haanen
- Subjects
CD40 ,biology ,business.industry ,MEDLINE ,General Medicine ,General Biochemistry, Genetics and Molecular Biology ,Clinical trial ,Antigen ,Immunology ,biology.protein ,Medicine ,Antibody ,business ,Immunologic memory - Abstract
A promising experimental vaccine strategy, just entering clinical trials, displays a deleterious effect in mice. Use of antibodies to CD40 seems to clamp down on the long-term ability of T cells to respond to antigen (pages 354–360).
- Published
- 2007
36. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma
- Author
-
Linnemann, Carsten, primary, van Buuren, Marit M, additional, Bies, Laura, additional, Verdegaal, Els M E, additional, Schotte, Remko, additional, Calis, Jorg J A, additional, Behjati, Sam, additional, Velds, Arno, additional, Hilkmann, Henk, additional, Atmioui, Dris el, additional, Visser, Marten, additional, Stratton, Michael R, additional, Haanen, John B A G, additional, Spits, Hergen, additional, van der Burg, Sjoerd H, additional, and Schumacher, Ton N M, additional
- Published
- 2014
- Full Text
- View/download PDF
37. Tumors hijack fetal enzyme, escape killer T cells
- Author
-
Schepers, Koen and Schumacher, Ton N M
- Abstract
Author(s): Koen Schepers [1]; Ton N M Schumacher [1] The immune system cannot be considered a model society: its basic rule seems to be 'kill anything that is perceived as [...]
- Published
- 2003
- Full Text
- View/download PDF
38. A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression
- Author
-
Ton N. Schumacher, Chien Fu Hung, Adriaan Bins, John B. A. G. Haanen, Monika C. Wolkers, Annelies Jorritsma, Tzyy Choou Wu, and Center of Experimental and Molecular Medicine
- Subjects
Dna delivery ,Immunity, Cellular ,Mice, Inbred BALB C ,Time Factors ,Vaccination ,Cellular Immunology ,General Medicine ,Biology ,Virology ,General Biochemistry, Genetics and Molecular Biology ,DNA vaccination ,Mice, Inbred C57BL ,Mice ,Drug Delivery Systems ,Antigen ,In vivo ,Immunity ,Influenza A virus ,Immunology ,Humoral immunity ,Vaccines, DNA ,Animals ,Luciferases ,Antigens, Viral - Abstract
Induction of immunity after DNA vaccination is generally considered a slow process. Here we show that DNA delivery to the skin results in a highly transient pulse of antigen expression. Based on this information, we developed a new rapid and potent intradermal DNA vaccination method. By short-interval intradermal DNA delivery, robust T-cell responses, of a magnitude sufficient to reject established subcutaneous tumors, are generated within 12 d. Moreover, this vaccination strategy confers protecting humoral immunity against influenza A infection within 2 weeks after the start of vaccination. The strength and speed of this newly developed strategy will be beneficial in situations in which immunity is required in the shortest possible time.
- Published
- 2004
39. In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens
- Author
-
Lisbet Sviland, Graham Jackson, Anne M. Dickinson, Ton N. Schumacher, Florry A. Vyth-Dreese, Tuna Mutis, Xiao-Nong Wang, Els Goulmy, John B. A. G. Haanen, Hematology laboratory, CCA - Cancer biology and immunology, and CCA - Cancer Treatment and quality of life
- Subjects
H-Y Antigen ,Graft vs Host Disease ,Peptide ,chemical and pharmacologic phenomena ,Human leukocyte antigen ,Biology ,In Vitro Techniques ,General Biochemistry, Genetics and Molecular Biology ,Minor Histocompatibility Antigens ,Graft vs Host Reaction ,Antigen ,Minor histocompatibility antigen ,medicine ,Cytotoxic T cell ,Humans ,Skin ,chemistry.chemical_classification ,Hematopoietic Stem Cell Transplantation ,General Medicine ,medicine.disease ,Neoplasm Proteins ,Transplantation ,Haematopoiesis ,Leukemia ,chemistry ,Immunology ,Oligopeptides ,T-Lymphocytes, Cytotoxic - Abstract
Minor histocompatibility antigens (mHags) are immunogenic peptides from polymorphic cellular proteins that induce strong T-cell responses after human leukocyte antigen (HLA)-matched, mHag-mismatched stem-cell transplantation. mHags with broad or limited tissue expression are target antigens for graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactivities. Separation of these activities is crucial for adoptive immunotherapy of leukemia without GvH disease. Therefore, using a skin-explant assay we investigated the in situ activities of cytotoxic T lymphocytes (CTLs) specific for the ubiquitously expressed mHag H-Y and for the hematopoietic-restricted mHags HA-1 and HA-2. H-Y-specific CTLs, visualized by tetrameric HLA-mHag peptide complexes, infiltrated male skin sections within 24 hours, induced severe GvH reactions of grade III-IV and produced high levels of IFN-gamma. In contrast, CTLs specific for the hematopoietic system-specific mHags HA-1 and HA-2 induced no or low GvH reactions above background and produced little or no interferon-gamma, unless the skin sections were preincubated with HA-1/HA-2 synthetic peptides. These results provide the first in situ dissection of GvH effects by mHag-specific CTLs and show that ubiquitously expressed mHags are the prime targets of GvH disease.
- Published
- 2002
40. In situ detection of virus- and tumor-specific T-cell immunity
- Author
-
Oomen Lc, Ton N. Schumacher, Ada M. Kruisbeek, J.B.A.G. Haanen, Florry A. Vyth-Dreese, van Oijen Mg, and Felicia H. Tirion
- Subjects
In situ ,Immunity, Cellular ,Microscopy, Confocal ,Protein Conformation ,T-Lymphocytes ,Receptor Aggregation ,Tumor specific ,Receptors, Antigen, T-Cell ,Mice, Transgenic ,General Medicine ,Biology ,Flow Cytometry ,Lymphoma, T-Cell ,Orthomyxoviridae ,Virology ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Major Histocompatibility Complex ,Mice ,Histocompatibility Antigens ,T cell immunity ,Animals - Published
- 2000
41. High-throughput identification of antigen-specific TCRs by TCR gene capture
- Author
-
Linnemann, Carsten, primary, Heemskerk, Bianca, additional, Kvistborg, Pia, additional, Kluin, Roelof J C, additional, Bolotin, Dmitriy A, additional, Chen, Xiaojing, additional, Bresser, Kaspar, additional, Nieuwland, Marja, additional, Schotte, Remko, additional, Michels, Samira, additional, Gomez-Eerland, Raquel, additional, Jahn, Lorenz, additional, Hombrink, Pleun, additional, Legrand, Nicolas, additional, Shu, Chengyi Jenny, additional, Mamedov, Ilgar Z, additional, Velds, Arno, additional, Blank, Christian U, additional, Haanen, John B A G, additional, Turchaninova, Maria A, additional, Kerkhoven, Ron M, additional, Spits, Hergen, additional, Hadrup, Sine Reker, additional, Heemskerk, Mirjam H M, additional, Blankenstein, Thomas, additional, Chudakov, Dmitriy M, additional, Bendle, Gavin M, additional, and Schumacher, Ton N M, additional
- Published
- 2013
- Full Text
- View/download PDF
42. Tumors hijack fetal enzyme, escape killer T cells
- Author
-
Ton N. Schumacher and Koen Schepers
- Subjects
chemistry.chemical_classification ,Pregnancy ,Fetus ,Tumor cells ,General Medicine ,Biology ,medicine.disease ,Natural killer T cell ,Tryptophan degradation ,General Biochemistry, Genetics and Molecular Biology ,medicine.anatomical_structure ,Enzyme ,chemistry ,Placenta ,embryonic structures ,Immunology ,medicine ,Cancer research ,Cytotoxic T cell ,reproductive and urinary physiology - Abstract
During pregnancy, tryptophan degradation in the placenta protects a growing fetus from attack by T cells. Tumor cells are now shown to exploit this unusual system to prevent rejection by tumor-specific cytotoxic T cells ( pages 1269–1274 ).
- Published
- 2003
43. Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy
- Author
-
Bendle, Gavin M, primary, Linnemann, Carsten, additional, Hooijkaas, Anna I, additional, Bies, Laura, additional, de Witte, Moniek A, additional, Jorritsma, Annelies, additional, Kaiser, Andrew D M, additional, Pouw, Nadine, additional, Debets, Reno, additional, Kieback, Elisa, additional, Uckert, Wolfgang, additional, Song, Ji-Ying, additional, Haanen, John B A G, additional, and Schumacher, Ton N M, additional
- Published
- 2010
- Full Text
- View/download PDF
44. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma.
- Author
-
Linnemann, Carsten, van Buuren, Marit M, Bies, Laura, Verdegaal, Els M E, Schotte, Remko, Calis, Jorg J A, Behjati, Sam, Velds, Arno, Hilkmann, Henk, Atmioui, Dris el, Visser, Marten, Stratton, Michael R, Haanen, John B A G, Spits, Hergen, van der Burg, Sjoerd H, and Schumacher, Ton N M
- Subjects
MELANOMA immunotherapy ,TUMOR antigens ,HIGH throughput screening (Drug development) ,CD4 antigen ,GENETIC mutation ,THERAPEUTICS - Abstract
Tumor-specific neo-antigens that arise as a consequence of mutations are thought to be important for the therapeutic efficacy of cancer immunotherapies. Accumulating evidence suggests that neo-antigens may be commonly recognized by intratumoral CD8+ T cells, but it is unclear whether neo-antigen-specific CD4+ T cells also frequently reside within human tumors. In view of the accepted role of tumor-specific CD4+ T-cell responses in tumor control, we addressed whether neo-antigen-specific CD4+ T-cell reactivity is a common property in human melanoma. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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45. Corrigendum: High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+T cells in human melanoma
- Author
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Linnemann, Carsten, van Buuren, Marit M, Bies, Laura, Verdegaal, Els M E, Schotte, Remko, Calis, Jorg J A, Behjati, Sam, Velds, Arno, Hilkmann, Henk, el Atmioui, Dris, Visser, Marten, Stratton, Michael R, Haanen, John B A G, Spits, Hergen, van der Burg, Sjoerd H, and Schumacher, Ton N M
- Published
- 2016
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46. Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial.
- Author
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de Gooyer PGM, Verschoor YL, van den Dungen LDW, Balduzzi S, Marsman HA, Geukes Foppen MH, Grootscholten C, Dokter S, den Hartog AG, Verbeek WHM, Woensdregt K, van den Broek JJ, Oosterling SJ, Schumacher TN, Kuhlmann KFD, Beets-Tan RGH, Haanen JBAG, van Leerdam ME, van den Berg JG, and Chalabi M
- Abstract
Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88-100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81-97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54-79%) pathologic complete responses. With a median follow-up of 8 months (range, 2-19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3-4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140 ., (© 2024. The Author(s).)
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- 2024
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47. In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens.
- Author
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Dickinson AM, Wang XN, Sviland L, Vyth-Dreese FA, Jackson GH, Schumacher TN, Haanen JB, Mutis T, and Goulmy E
- Subjects
- Graft vs Host Disease etiology, Graft vs Host Disease immunology, Graft vs Host Disease pathology, H-Y Antigen metabolism, Hematopoietic Stem Cell Transplantation adverse effects, Humans, In Vitro Techniques, Neoplasm Proteins metabolism, Oligopeptides metabolism, Skin immunology, Skin pathology, T-Lymphocytes, Cytotoxic pathology, Graft vs Host Reaction immunology, Minor Histocompatibility Antigens metabolism, T-Lymphocytes, Cytotoxic immunology
- Abstract
Minor histocompatibility antigens (mHags) are immunogenic peptides from polymorphic cellular proteins that induce strong T-cell responses after human leukocyte antigen (HLA)-matched, mHag-mismatched stem-cell transplantation. mHags with broad or limited tissue expression are target antigens for graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactivities. Separation of these activities is crucial for adoptive immunotherapy of leukemia without GvH disease. Therefore, using a skin-explant assay we investigated the in situ activities of cytotoxic T lymphocytes (CTLs) specific for the ubiquitously expressed mHag H-Y and for the hematopoietic-restricted mHags HA-1 and HA-2. H-Y-specific CTLs, visualized by tetrameric HLA-mHag peptide complexes, infiltrated male skin sections within 24 hours, induced severe GvH reactions of grade III-IV and produced high levels of IFN-gamma. In contrast, CTLs specific for the hematopoietic system-specific mHags HA-1 and HA-2 induced no or low GvH reactions above background and produced little or no interferon-gamma, unless the skin sections were preincubated with HA-1/HA-2 synthetic peptides. These results provide the first in situ dissection of GvH effects by mHag-specific CTLs and show that ubiquitously expressed mHags are the prime targets of GvH disease.
- Published
- 2002
- Full Text
- View/download PDF
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