ITCC-P4 has started as a public-private consortium project funded through the ‘Innovative Medicines Initiative’ (2017-2023). The consortium with 21 partners from 8 countries has established ≈400 new patient-derived in vivo preclinical models of high-risk paediatric solid tumours and leukaemias supported by a comprehensive database harbouring corresponding molecular and pharmacological characterization data. Under umbrella of the consortium project, the sustainable non-profit legal entity ITCC-P4 gGmbH was established under German Law in April 2023 to make these models available for preclinical drug testing both for industry and academic customers. 

Project Term: January 1st, 2017 - December 31st, 2023

Funding: € 19.1 Mio

Learn more about the ITCC-P4 project below!

Project Outline

Project Partners

Project-related News and Publications

WP-lead: Stefan Pfister (DKFZ) and Lou Stancato (Eli Lilly)
Co-lead: Hubert Caron (Roche), Gilles Vassal (IGR)

This WP has been responsible for the overall management of the consortium. This included the organization of regular telephone conferences and face-to-face meetings, communication between academic partner sites, SMEs and industry, the monitoring of the adherence to budgets and milestones, the governance of sample and data access, the coordination of reports, the preparation of consortium publications together with the respective participants, the representation of the consortium at conferences, and the embedding in ITCC and other participating networks.

WP-lead: Jan Molenaar (PMC) and Hubert Caron (Roche)

In this work package we aimed to perform a systematic validation of targeted compounds and corresponding actionable genes and pathways in the different pediatric solid tumor entities prior to the in vitro and in vivo testing phase using relevant literature and the existing (epi)genomic and transcriptomic datasets of all entities in question. We also mapped these with the portfolios of the participating pharma partners to enable a first prioritization of compounds for in vivo testing. With this approach, we were able to select tumor types that would most likely respond to the targeted interventions; this would result in more efficient use of the PDX systems. The pipeline encompassed a systematic literature review followed by in silico analysis of the actionable events.

WP-lead: Marcel Kool (DKFZ) and David Shields (Pfizer)
Co-lead: Johannes H. Schulte (Charite), Gudrun Schleiermacher (IC), Sara Colombetti (Roche), Jan-Henning Klusmann (MLU), Christina Guttke (Janssen)

One of the central activities of the consortium was the development of representative and robust preclinical models accurately reflecting human disease and providing efficient platforms for in vivo functional compound testing (WP5). Prominent to WP3 was the development of a sustainable infrastructure for generation and use of Patient-Derived Models (PDMs) (Patient-Derived Xenograft (PDX) and organoid models) and Genetically Engineered Mouse Models (GEMMs). Robust genomic characterization of all established models was conducted, including cross-species human (primary/PDX/organoid): mouse (GEMM) comparisons. Several specialized academic labs, SMEs (EPO, XenTech) and EFPIA partners (Charles River) generated around 400 PDX models, representing the major paediatric solid and liquid tumor entities.
To more faithfully replicate the biology of the brain tumors, orthotopic (intracranial) engraftment was conducted using stereotactic injections of patient-derived or GEMM-derived tumor material. For all other solid tumors, flank engraftment was performed. For the leukemias orthotopic (in case of leukaemias bone marrow) engraftment was conducted. To assess the predictive power of therapeutic testing studies using ex vivo organoid or PDX cultures, a proof-of-concept panel of 40 organoid lines from solid tumors and 25 leukemic PDX, representing up to five tumor types were established at PMC, Newcastle and Zuerich.

A comprehensive molecular characterization of all primary tumor material, matching germline samples, derived models and GEMMs was performed to enable full interpretation of any preclinical results. This was done at the DKFZ, Institut Curie and PMC. The comprehensive molecular characterization included high-coverage, whole-exome and low-coverage, whole-genome sequencing of all PDMs and their matching primary tumors and germline DNA, as well as RNAseq, Affymetrix gene expression profiling and DNA methylation profiling.

WP-lead: Gilles Vassal (ITCC) and Silvia Chioato (PFZ)
Co-lead: Birgit Geoerger (IGR), Olaf Witt (DKFZ), Richard Vart (LILLY) and Louise Hayes (ROCHE)

ITCC-P4 aimed to generate a science-based regulatory consensus endorsed by the EMA and PDCO on the biological and preclinical information required to support a pediatric investigation plan for an oncology medicinal product. This would eventually support the development of an EMA guideline.
ITCC-P4 took advantage of the unique combination of distinct and synergistic expertises of its academic, CRO and EFPIA partners with preclinical proof-of-concept (POC) testing in cancer models and with Health Authority interactions and Parent’s organisations to establish the science-based regulatory consensus on POC data-packages and minimally-required datasets.
The project and then the platform, would generate biological and preclinical data for oncology medicinal products that are considered for pediatric development. This information along with the evaluation of the therapeutic needs of the young population contributed to the rationale for a pediatric investigation plan. In addition, the PDX platform would generate comparative preclinical data for compounds targeting the same molecular pathway or sharing the same or similar mechanism of action. This could facilitate the identification of  the potentially best and more relevant oncology medicinal products.
Data from the platform could be used in pediatric drug development strategy forums to discuss how best to develop innovative compounds for pediatric malignancies.

WP4 would thus contribute to build the regulatory basis for the process of identifying drugs more likely to be effective in pediatric malignancies and which should be developed in children. It aimed to provide the regulatory consensus guideline that would improve and streamline the efficiency of drug development for children with cancer.

WP-lead: Dieter Zopf (Bayer) and Jens Hofmann (EPO)
Co-lead: Sara Colombetti (Roche), Olaf Heidenreich (PMC), Diana Alvarez Arias (Janssen)

The goal of WP5 was the testing of compounds from all consortium members (academic and industrial) in a limited number of approved and validated testing sites by a quality-assured methodology, including single drugs with readouts of ‘biological efficacy’. The main drug testing component on PDX was performed in a standardized fashion exclusively at the SMEs and at two EFPIA partners (Charles River and PharmaMar) to ensure quality and comparability of the data. The proof-of-concept drug testing in organoids was exclusively done at the PMC (where the organoids also were established); that for leukemia PDX in the three academic centres Newcastle, Zurich and PMC.

The respective disease entity groups selected a panel of SOC and investigational drugs. Three standard-of-care drugs and five selected targeted therapy were evaluated for their anti-tumor activity in vivo. Exploratory combination studies were performed based on the results of WP 2 and 5. Combinations included small molecules/targeted therapies/new drugs with each other or with chemotherapy or radiotherapy (e.g. to disrupt the blood-brain-barrier).
All data was rapidly distributed to the consortium. Response evaluation provided guidance for clinical tumor treatment, to support the identification of suitable combination partners and to uncover potential resistance mechanism through correlation with molecular data generated in WP3.

WP-lead: Jan Koster (AMC), Louis Stancato (Eli Lilly)
Co-lead: Natalie Jäger (DKFZ)

The aim of WP6 was to estabish a centralized data repository including results of the project such as precompetitive model characteristics (i.e., all data associated with model molecular and pharmacological characterization using commercially-available agents) and SOC testing data with custom informatics tools to visualize and analyze data.
For dissemination of processed genomics and drug-testing data, the consortium proposed to build on the existing IT infrastructure that is available at the AMC (R2; r2.amc.nl) and which is used extensively in the pediatric cancer research community: R2 already has an extensive track record in providing biomedical researchers insight into their high-throughput data (390+ Pubmed citations and serving data on 100,000+ samples, Aug. 2016). R2 allows for many different types of investigations on pre-processed genomics data ranging from correlative/differential analyses up to working with whole genome sequencing results in real-time. It contains a wealth of analysis and visualizations that are easily accessible. In addition, R2 hosts a growing set of tools for integrative analyses over different types of data (e.g. correlating gene expression to DNA methylation, DNA copy-number, or mutation status). 

R2 hosted pre-processed genomics data in various ways to allow for ‘browsing’, analysis, and visualization of the diverse types of information obtained throughout this project.

WP-lead: Gilles Vassal (Gustave Roussy) with Gustave Roussy Transfer, Lou Stancato (Eli Lilly) and Hubert Caron (ROCHE)

The ultimate goal was to build a post-IMI2 sustainable infrastructure that would provide the biological and preclinical data to identify new oncology drugs to be developed in the pediatric population in order to adequately address the needs of children and adolescents with cancer. During the years of IMI-2 funding, a comprehensive panel of fully molecularly and pharmacologically well characterized preclinical pediatric cancer models was set up in order to provide the preclinical information required to contribute to the best choice of innovative compounds to be further developed in children, as single agent and in combination. All standard operating procedures were established, as well as a biobank and a database of molecular and pharmacological data.

WP7 designed and implemented a sustainable platform to ensure the pediatric testing infrastructure continues after the end of the project. ITCC-P4 partners, amongst others, discussed the following principles:

• The platform would run commercial activities for pharmaceutical companies and would be accessible for academic institutions.
• The platform would not sell preclinical models, but rather would focus on the ex vivo and in vivo testing in these models
• The platform would set up secured access to data and models generated during the project, to provide fee-for-service on the preclinical models and generation of data through a quality-assured program respecting ethical rules on animal testing.

Target Actionability Review: a systematic evaluation of replication stress as a therapeutic target for paediatric solid malignancies

European Journal of Cancer 2021, 162: 107-117 (https://doi.org/10.1016/j.ejca.2021.11.030)

International Consensus on Minimum Preclinical Testing Requirements for the Development of Innovative Therapies For Children and Adolescents with Cancer.

Molecular Cancer Therapeutics 2021, 20: 1462–8 (https://doi.org/10.1158/1535-7163.MCT-20-0394)

Systematic target actionability reviews of preclinical proof-of-concept papers to match targeted drugs to paediatric cancers.

European Journal of Cancer 2020, 160:168-181 (https://doi.org/10.1016/j.ejca.2020.01.027)

Single-Cell RNA-Seq Reveals Cellular Hierarchies and Impaired Developmental Trajectories in Pediatric Ependymoma.

Cancer Cell 2020, 38(1):44-59.e9. (https://doi.org/10.1016/j.ccell.2020.06.004)

Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity.

Nature Communication 2020, 11(1):4629. (https://doi.org/10.1038/s41467-020-18388-7)

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.

Nature Medicine 2020, May 26(5):712-719. (https://doi.org/10.1038/s41591-020-0821-8)

Crossing Oceans: Preclinical Collaboration to Improve Pediatric Drug Development.

American Society of Clinical Oncology Educational Book. 2020, 40:1-8. (https://doi.org/10.1200/EDBK_278893)

Targeting fibroblast growth factor receptors to combat aggressive ependymoma.

Acta Neuropathologica 2021 Aug;142(2):339-360. (https://doi.org/10.1007/s00401-021-02327-x)

Integrated molecular characterization of patient-derived models reveals therapeutic strategies for treating CIC-DUX4 sarcoma.

Cancer Research 2022, 82(4):708-720. (https://doi.org/10.1158/0008-5472.CAN-21-1222)

Prognostic value of patient-derived xenograft engraftment in pediatric sarcomas.

Journal of Pathology–clinical research 2021, 7:338-349. (https://doi.org/10.1002/cjp2.210)

A biobank of patient-derived pediatric brain tumor models.

Nature Medicine 2018, 24: 1752–1761. (https://doi.org/10.1038/s41591-018-0207-3)

PCLN-05. A BIOBANK OF PATIENT-DERIVED MOLECULARLY CHARACTERIZED ORTHOTOPIC PEDIATRIC BRAIN TUMOR MODELS FOR PRECLINICAL RESEARCH.

Neuro-Oncology 2018, 20: 155 (https://doi.org/10.1093/neuonc/noy059.574)

ROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity.

Journal of Experimental & Clinical Cancer Research 2019, 38: 503 (https://doi.org/10.1186/s13046-019-1506-3)

TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAFV600E/TERT promoter double-mutated glioma.

Acta Neuropathologica Communications 2019, 7: 128 (https://doi.org/10.1186/s40478-019-0775-6)

Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors.

Translational Oncology 2020, 3: 221-232 (https://doi.org/10.1016/j.tranon.2019.09.013)

Increased Anaplastic Lymphoma Kinase Activity Induces a Poorly Differentiated Thyroid Carcinoma in Mice.

Thyroid 2020, 29/10: 1438-1446 (https://doi.org/10.1089/thy.2018.0526)

Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma.

Cancer Letters 2019, 445: 24-33 (https://doi.org/10.1016/j.canlet.2018.12.012)

Ewing Sarcoma PDX Models.

Ewing Sarcoma - Methods and Protocols 2020, 2226: 223-242 (https://doi.org/10.1007/978-1-0716-1020-6_18)

Molecular and preclinical evaluation of patient-derived orthotopic xenograft models of pediatric brain tumors.

Dissertation, Univesity of Heidelberg 2018. (https://d-nb.info/1199620114)