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Clinical MedicineIn-Press PreviewImmunologyOncology Open Access | 10.1172/jci.insight.186062

Multimodal integration of blood RNA and ctDNA reflects response to immunotherapy in metastatic urothelial cancer

Sandra van Wilpe,1 Davide Croci,2 Sara S. Fonseca Costa,2 Iris B.A.W. te Paske,1 Sofie H. Tolmeijer,1 Jolique van Ipenburg,3 Leonie I. Kroeze,3 Simona Pavan,2 Sylvain Monnier-Benoit,2 Guido Coccia,2 Noushin Hadadi,2 Irma M. Oving,4 Tineke J. Smilde,5 Theo van Voorthuizen,6 Marieke Berends,7 Mira D. Franken,1 Marjolijn J.L. Ligtenberg,4 Sahar Hosseinian Ehrensberger,2 Laura Ciarloni,2 Pedro Romero,2 and Niven Mehra1

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

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

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

Find articles by Fonseca Costa, 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

Find articles by te Paske, 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

Find articles by Tolmeijer, 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

Find articles by van Ipenburg, J. 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

Find articles by Kroeze, L. 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

Find articles by Pavan, 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

Find articles by Monnier-Benoit, 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

Find articles by Coccia, G. 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

Find articles by Hadadi, N. 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

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

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

Find articles by van Voorthuizen, 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

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

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

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

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

Find articles by Ciarloni, L. 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

Find articles by Romero, P. 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

Find articles by Mehra, N. in: JCI | PubMed | Google Scholar

Published January 30, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.186062.
Copyright © 2025, van Wilpe et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 30, 2025 - Version history
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Abstract

BACKGROUND. Previously, we demonstrated that changes in circulating tumor DNA (ctDNA) are promising biomarkers for early response prediction (ERP) to immune checkpoint inhibitors (ICI) 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 a discovery (N=29), test (N=29) and validation set (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 signalling during treatment in the CB group, contrary to N-CB patients. Based on these differences a 10-gene RNA model was generated, reaching a SN and SP of 73% and 79% in the test and 67% and 67% in the validation set for predicting N-CB. Multimodal model integration led to superior performance with a SN and SP of 79% and 100% 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.

TRIAL REGISTRATION. 2016-3060, 2020-6778

FUNDING. Eurostars grant E! 114908 - PRECISE, Paul Speth Foundation (Bullseye project)

Supplemental material

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  • Version 1 (January 30, 2025): In-Press Preview
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