Data availability
Raw sequencing data from patient samples. The whole-exome and transcriptome sequencing data generated in this study from patient tumour and matched healthy tissue samples (n = 54) have been deposited in the German Human Genome-Phenome Archive (GHGA) under the accession code GHGAS41175626365361. These data are available under restricted access due to data privacy regulations and ethical requirements related to personal data from a vulnerable patient population. Access to the data is granted only to qualified researchers for non-commercial research use upon approval of a controlled access request. Requests for data access can be submitted via the GHGA Data Portal [[https://data.ghga.de](https://data.ghga.d…
Data availability
Raw sequencing data from patient samples. The whole-exome and transcriptome sequencing data generated in this study from patient tumour and matched healthy tissue samples (n = 54) have been deposited in the German Human Genome-Phenome Archive (GHGA) under the accession code GHGAS41175626365361. These data are available under restricted access due to data privacy regulations and ethical requirements related to personal data from a vulnerable patient population. Access to the data is granted only to qualified researchers for non-commercial research use upon approval of a controlled access request. Requests for data access can be submitted via the GHGA Data Portal [https://data.ghga.de] or by contacting ppk-c@charite.de. Applications are reviewed by the Data Access Committee (DAC) at Charité - Universitätsmedizin Berlin in coordination with GHGA, and responses and data access are typically provided within 3–4 weeks. Approved applicants are required to sign a Data Use Agreement (DUA) governed by Charité - Universitätsmedizin Berlin. A copy of the DUA is available upon request from the corresponding author or from the DAC. Users of these data are requested to cite this study in any resulting publications. Data reuse is limited to non-commercial research purposes. The raw whole-genome sequencing data from 20 neuroblastoma primary tumours with matched controls used to call structural variants and reconstruct extrachromosomal DNA (ecDNA) elements in this study are publicly available in the European Genome–Phenome Archive (EGA) under accession numbers:
EGAS00001001308 [https://ega-archive.org/studies/EGAS00001001308], EGAS00001004022, and EGAS00001006983. The processed structural variant calls and ecDNA reconstructions supporting this study’s conclusions are publicly available in Zenodo under https://doi.org/10.5281/zenodo.8032024, corresponding to the published whole-genome sequencing dataset of the discovery cohort by Rodríguez-Fos et al., (Cell Genomics, 2023)78.
Cell line sequencing data. Sequencing data generated from neuroblastoma cell lines in this study have been deposited in the NCBI Sequence Read Archive (SRA) under BioProject accession number PRJNA1292401. The datasets are publicly available and can be accessed directly through the project webpage or by entering the accession number in the NCBI SRA Run Selector.
DepMap datasets. Publicly available sequencing and dependency datasets from the Cancer Dependency Map (DepMap) were used in this study:
DepMap 23Q4 [https://doi.org/10.25452/figshare.plus.24667905.v2]69;
DepMap 22Q2 [https://doi.org/10.6084/m9.figshare.19700056.v2]68.
DepMap 20Q4 [https://doi.org/10.6084/m9.figshare.13237076.v4]67;
Other data. All other data supporting the findings of this study are available within the article or its Supplementary Information. Source data are provided with this paper.
Code availability
The CancerPAM bioinformatics pipeline used in this study, including sample data, is available in the Code Ocean repository under accession number 7671597 under https://doi.org/10.24433/CO.2312035.v179. The ecDNA/SV Breakpoint-CRISPR pipeline is available in the Zenodo repository under accession number 17209179 under https://doi.org/10.5281/zenodo.1720917980. The Python implementation of the CancerPAM statistical tumour off-target risk model is available in the Zenodo repository under accession number 17209430 under https://doi.org/10.5281/zenodo.1720943081.
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Acknowledgements
This work was supported by Berliner Krebsgesellschaft (grant number LAFF202008 to M.L.) and KINDerLEBEN e.V. Berlin (to M.L.). Additional support was provided by Charité - Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin (AdHoc Booster Grant to D.W. and M.L.). M.L. participates in the BIH Charité Clinician Scientist Program, funded by Charité - Universitätsmedizin Berlin and the BIH. A.K. participates in the BIH Charité Advanced Clinician Scientist Pilot Program, also funded by Charité - Universitätsmedizin Berlin and the BIH. The authors thank Silke Schwiebert and Anika Winkler for their technical support with the experiments; Michael C. Jensen for providing the L1CAM-CAR T cell construct; Nikolaus Rajewsky for his support as a scientific mentor within the framework of the BIH Charité Clinician Scientist Program; and Kathy Astrahantseff for manuscript proofreading and editorial advice. Parts of Figs. 1, 5, 6, 7 and Supplementary Figs. 16 and 19 were created with BioRender.com.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Author information
Authors and Affiliations
Department of Pediatric Oncology and Haematology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin, Germany
Michael Launspach, Julia Macos, Shoaib Afzal, Janik Hohmann, Marc L. Appis, Maximilian Pilgram, Stefanie Beez, Emily Ohlendorf, Karin Töws, Lena Andersch, Marvin Jens, Felix Zirngibl, Jonas Kath, Elias Rodriguez-Fos, Kathleen Anders, Anton G. Henssen, Angelika Eggert & Annette Künkele 1.
Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
Michael Launspach, Julia Macos, Shoaib Afzal, Marc L. Appis, Emily Ohlendorf, Karin Töws, Lena Andersch, Kathleen Anders, Angelika Eggert & Annette Künkele 1.
German Cancer Consortium (DKTK), partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany
Michael Launspach, Lena Andersch, Kathleen Anders, Anton G. Henssen, Angelika Eggert & Annette Künkele 1.
Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Berlin, Germany
Michael Launspach, Dimitrios L. Wagner, Angelika Eggert & Annette Künkele 1.
Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
Marc L. Appis 1.
Cellbricks GmbH, Berlin, Germany
Casper F. T. van der Ven & Chahrazad Lachiheb 1.
BIH Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany
Jonas Kath & Dimitrios L. Wagner 1.
EPO Berlin-Buch GmbH, Berlin, Germany
Maria Stecklum 1.
Experimental and Clinical Research Center (ECRC) of the MDC and Charité - Universitätsmedizin Berlin, Berlin, Germany
Elias Rodriguez-Fos & Anton G. Henssen 1.
Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
Dimitrios L. Wagner 1.
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
Dimitrios L. Wagner 1.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
Dimitrios L. Wagner 1.
Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
Dimitrios L. Wagner 1.
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
Anton G. Henssen & Ralf Kühn 1.
University Medicine Essen, Essen, Germany
Angelika Eggert
Authors
- Michael Launspach
- Julia Macos
- Shoaib Afzal
- Janik Hohmann
- Marc L. Appis
- Maximilian Pilgram
- Stefanie Beez
- Emily Ohlendorf
- Casper F. T. van der Ven
- Chahrazad Lachiheb
- Karin Töws
- Lena Andersch
- Marvin Jens
- Felix Zirngibl
- Jonas Kath
- Maria Stecklum
- Elias Rodriguez-Fos
- Kathleen Anders
- Dimitrios L. Wagner
- Anton G. Henssen
- Ralf Kühn
- Angelika Eggert
- Annette Künkele
Contributions
M.L. conceived and designed the study, acquired funding, and wrote the manuscript with input from all authors. M.L., J.H., M.L.A. and M.J. developed the CancerPAM pipeline. M.L., J.M., S.A., S.B., M.P., E.O., C.V., C.L., L.A., K.T., M.L.A., J.K. and M.S. performed the experiments. M.L., J.M., S.A., J.H., S.B., M.P., E.O. and C.V. analysed the data. M.L., M.J., C.V., L.A., K.T., F.Z., J.K., M.S., E.R., K.A., D.L.W., A.G.H., R.K. and A.K. developed the methodology. RK, AE and AK supervised the study. All authors contributed equitably to the work and were given the opportunity to participate in data analysis, interpretation, and manuscript preparation. The collaboration involves institutions from multiple countries and disciplines, emphasising transparency, inclusivity, and equitable recognition of scientific contributions.
Corresponding author
Correspondence to Michael Launspach.
Ethics declarations
Competing interests
M.L. reports in-kind support (reagents and services) related to CRISPR-Cas gene editing and digital PCR from QIAGEN. This support did not influence the design, execution, analysis, or interpretation of the present study. D.L.W.’s laboratory at Charité has received in-kind reagents/services related to CRISPR–Cas gene editing from Integrated DNA Technologies (IDT) and GenScript Inc. None of the companies or intellectual property described influenced the design, execution, or interpretation of this study. Unrelated to this work, D.L.W. is named as an inventor on patent applications related to genome editing and cell therapies and is a co-founder of TCBalance Biopharmaceuticals GmbH. All other authors declare no competing interests.
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Cite this article
Launspach, M., Macos, J., Afzal, S. et al. Personalized CRISPR knock-in cytokine gene therapy to remodel the tumor microenvironment and enhance CAR T cell therapy in solid tumors. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67328-w
Received: 01 April 2025
Accepted: 25 November 2025
Published: 09 December 2025
DOI: https://doi.org/10.1038/s41467-025-67328-w