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Clinical Research and Public HealthImmunologyOncology
Open Access | 
10.1172/jci.insight.186062
1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
Find articles by van Wilpe, S. in: JCI | PubMed | Google Scholar
1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
Find articles by Croci, D. in: JCI | PubMed | Google Scholar
1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
Find articles by Oving, I. in: JCI | PubMed | Google Scholar
1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
Find articles by Smilde, T. in: JCI | PubMed | Google Scholar
1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
Find articles by Berends, M. in: JCI | PubMed | Google Scholar
1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
Find articles by Franken, M. in: JCI | PubMed | Google Scholar
1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
Find articles by Ligtenberg, M. in: JCI | PubMed | Google Scholar
1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
Find articles by Hosseinian Ehrensberger, S. in: JCI | PubMed | Google Scholar
1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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1Medical Oncology Department, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
2Novigenix SA, Epalinges, Switzerland.
3Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
4Department of Medical Oncology, Ziekenhuisgroep Twente, Almelo, Netherlands.
5Department of Medical Oncology, Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch, Netherlands.
6Department of Medical Oncology, Rijnstate, Arnhem, Netherlands.
7Department of Medical Oncology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands.
8Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands.
Address correspondence to: Davide Croci, Route de la Corniche 3, Phenyl Building, 1066 Epalinges, Switzerland. Email: davide.croci@novigenix.com. Or to: Sandra van Wilpe, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. Email: Sandra.vanWilpe@radboudumc.nl.
Authorship note: SVW, DC, and SSFC contributed equally to this work.
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Authorship note: SVW, DC, and SSFC contributed equally to this work.
Published January 30, 2025 - More info
Published in Volume 10, Issue 5 on March 10, 2025
Abstract
BACKGROUND. Previously, we demonstrated that changes in circulating tumor DNA (ctDNA) are promising biomarkers for early response prediction (ERP) to immune checkpoint inhibitors (ICIs) in metastatic urothelial cancer (mUC). In this study, we investigated the value of whole-blood immunotranscriptomics for ERP-ICI and integrated both biomarkers into a multimodal model to boost accuracy.
METHODS. Blood samples of 93 patients were collected at baseline and after 2–6 weeks of ICI for ctDNA (n = 88) and immunotranscriptome (n = 79) analyses. ctDNA changes were dichotomized into increase or no increase, the latter including patients with undetectable ctDNA. For RNA model development, the cohort was split into discovery (n = 29), test (n = 29), and validation sets (n = 21). Finally, RNA- and ctDNA-based predictions were integrated in a multimodal model. Clinical benefit (CB) was defined as progression-free survival beyond 6 months.
RESULTS. Sensitivity (SN) and specificity (SP) of ctDNA increase for predicting non-CB (N-CB) was 59% and 92%, respectively. Immunotranscriptome analysis revealed upregulation of T cell activation, proliferation, and interferon signaling during treatment in the CB group, in contrast with N-CB patients. Based on these differences, a 10-gene RNA model was generated, reaching an SN and SP of 73% and 79%, respectively, in the test and 67% and 67% in the validation set for predicting N-CB. Multimodal model integration led to superior performance, with an SN and SP of 79% and 100%, respectively, in the validation cohort.
CONCLUSION. The combination of whole-blood immunotranscriptome and ctDNA in a multimodal model showed promise for ERP-ICI in mUC and accurately identified patients with N-CB.
FUNDING. Eurostars grant E! 114908 - PRECISE, Paul Speth Foundation (Bullseye project).
IntroductionIn the last decade, immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) or its major ligand (PD-L1) have become one of the main treatment modalities for patients with irresectable or metastatic urothelial cancer (mUC). In 2017, pembrolizumab became the standard-of-care treatment for patients with mUC following progression on first-line platinum-based chemotherapy based on results of the KEYNOTE-045 trial (1). Since then, the use of ICIs in patients with mUC has shifted to the first-line and maintenance setting. In 2021, maintenance therapy with avelumab became available for patients with a response or stable disease to first-line platinum-based chemotherapy (2). Very recently, the combination of pembrolizumab and antibody-drug conjugate enfortumab-vedotin (EV) became the new standard-of-care first-line treatment based on results of the EV-302 trial. In this phase III clinical trial, pembrolizumab-EV prolonged median overall survival (mOS) from 16.1 to 31.5 months compared with platinum-based chemotherapy in the first-line setting (3, 4). Another new first-line treatment option for patients who are eligible for cisplatin is the combination of nivolumab with cisplatin and gemcitabine, which has shown an OS advantage compared with cisplatin-based chemotherapy alone in the CheckMate 901 trial (5).
Although ICI-containing combination therapies have proven their superiority compared with first-line chemotherapy in unselected fit patients (3–5), it is anticipated that ICI monotherapy will continue to be an important treatment modality. First, ICI monotherapy will continue to play an important role in the treatment of frail or elderly patients with mUC because of the high toxicity associated with combination therapies. In addition, there might be a role for ICI monotherapy in biomarker-selected patients who are predicted to durably benefit from ICI monotherapy, regardless of frailty, to avert unnecessary toxicity and costs.
Responses to ICIs in mUC are heterogeneous. Specifically, ICI monotherapy induces objective response in 20%–25% of mUC patients receiving first- or second-line ICIs and approximately 10% are still progression-free after 4 years (6, 7). These latter patients might not derive extra benefit from the addition of EV or chemotherapy. To personalize treatment decisions in mUC, there is a need for high-precision biomarkers that can identify patients who benefit from ICI monotherapy. Several baseline tumor biomarkers, including tumor mutational burden (TMB), PD-L1 expression, and tumor immune cell infiltration, have been associated with response to ICIs in mUC (8–12). Although PD-L1 expression enriches for responders to first-line ICIs in cisplatin-ineligible patients and is used to select patients for ICIs over carboplatin-based chemotherapy, none of these standalone biomarkers are accurate enough to predict response to ICIs.
In recent years, circulating tumor DNA (ctDNA) measurement has emerged as a method to monitor treatment response (13–15). The ctDNA level correlates well with tumor burden and can, therefore, be used as a noninvasive tool to monitor treatment response. We previously demonstrated that increases in ctDNA after 3–6 weeks are a promising biomarker for the early identification of disease progression to ICIs in mUC (15). However, ctDNA does not capture all host-related and tumor microenvironment–related factors that play a role in antitumor immunity. Multimodal biomarkers capturing both tumor and immune signals might improve biomarker accuracy.
In this study, we searched for on-treatment (OT) biomarkers that accurately identify patients without clinical benefit (N-CB), so that those with N-CB can be considered for other, more effective (combinatorial) therapies, while unwanted treatment discontinuation in patients with clinical benefit (CB) is avoided. We analyzed ctDNA and the peripheral blood immunotranscriptome in baseline (BL) and early OT samples of mUC patients treated with ICI monotherapy. We show that early changes in the peripheral blood immunotranscriptome are associated with response to ICIs and can be utilized to predict CB. Additionally, we demonstrate the synergy between ctDNA and whole-blood RNA-sequencing (RNA-seq) data, by combining the 2 approaches in a multimodal model for early response prediction.
ResultsClinical characteristics of the ICI-treated mUC patient cohort. To longitudinally and noninvasively monitor response to ICIs and to discover biomarkers predictive of CB, we collected blood liquid biopsies (LBx) from a total of 93 mUC patients treated with pembrolizumab (n = 72), nivolumab (n = 7), or avelumab (n = 14) (Figure 1A, Supplemental Figure 1A, and Table 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.186062DS1). Specifically, BL blood LBx were collected before ICI therapy initiation, while OT LBx were collected after cycle 1 or 2 (2–6 weeks). LBx samples were used for ctDNA and bulk whole-blood RNA-seq analysis (see Methods for details). We collected paired BL and OT ctDNA data for 88 patients and RNA-seq data for 79 patients, 74 of whom had both ctDNA and RNA data. Moreover, archival tumor tissue (formalin-fixed, paraffin embedded [FFPE]) was used to determine PD-L1 combined positive score (CPS) (n = 62) and TMB (n = 78) (Table 1). Of note, for RNA-seq analysis and modeling, patients were distributed in separate discovery, testing, and validation cohorts for optimal data analysis (Supplemental Figure 1A). Clinical endpoint was clinical benefit at 6 months, defined as radiological and clinical progression-free survival (PFS) at or beyond 6 months from treatment initiation (Supplemental Figure 1B). Out of the 93 patients included, 42 patients experienced CB and 51 did not (N-CB). Clinical characteristics are described in Table 1.
Figure 1Circulating tumor DNA (ctDNA) dynamics predicts clinical benefit (CB) to immune checkpoint inhibitor (ICI) therapy in metastatic urothelial cancer (mUC) patients. (A) Sample collection and analysis schematic: mUC patients were treated with an ICI (pembrolizumab, nivolumab, or avelumab) until disease progression. Blood was collected at baseline (BL, before cycle 1) and on-treatment (OT, after 2–6 weeks) for both ctDNA and RNA analysis. The primary endpoint was CB. This was defined as progression-free survival (PFS) for at least 6 months. (B) Kaplan-Meier (KM) curve comparing the PFS of patients with PD-L1–positive tumor (orange curve, PD-L1 combined positive score < 10) and patients with PD-L1–negative tumor (green curve, PD-L1 combined positive score < 10). (C) KM curve comparing the PFS of patients with a high tumor mutational burden (TMB) (orange curve, TMB ≥ 10 mutations/Mb) and TMB low patients (green curve, TMB < 10 mutations/Mb). (D) KM curve comparing the PFS of ctDNA-based patient stratification. The predicted CB population (orange curve) contains patients who had a decrease in ctDNA fraction from BL to OT or undetected at both time points. The predicted non-clinical benefit (N-CB, green curve) population contains patients where the ctDNA fraction increased from BL to OT or was stable. P values were determined by a Mantel-Haenszel test. HR, hazard ratio; CI, confidence interval.
Table 1Baseline patient characteristics
ctDNA profiling outperforms conventional tumor biomarkers for prediction of N-CB in ICI-treated mUC patients. High TMB and PD-L1 expression in the tumor have previously been associated with CB to ICIs (16, 17). We, therefore, assessed whether these 2 tumor biomarkers could help stratify the cohort into patients with or without CB (Figure 1, B and C). High PD-L1 expression was defined as a CPS of 10 or higher, in line with what is used in the clinic to select cisplatin-ineligible mUC patients for first-line ICIs. There was a weak trend, but no significant association, between a CPS of 10 or higher and longer PFS (Figure 1B). High TMB, defined as 10 mutations or more per megabase, was significantly associated with improved PFS (Figure 1C), but low TMB had only 80% sensitivity and 43% specificity to predict N-CB. The
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