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ITCC Pediatric Preclinical POC Platform – Sofia ref.: 116064

Periodic Reporting for period 6 - ITCC-P4 (ITCC Pediatric Preclinical POC Platform – Sofia ref.: 116064)

Período documentado: 2022-01-01 hasta 2022-12-31

Cancer remains the leading cause of disease-related death in children after the first year of life. For the ~25% of children who experience relapses of their solid tumours, usually after intensive first-line therapy, curative treatment options are scarce. Preclinical drug testing to identify promising treatment options that match tumour biology is hampered by the fact that i) molecular genetic data on paediatric solid tumours from relapsed patients and thus our understanding of tumour evolution and therapy resistance are very limited and ii) for many of the high-risk entities, no appropriate and molecularly well characterized patient-derived models and/or genetic mouse models are available. Thus, quality-assured upfront preclinical testing of novel molecularly matching compounds in a (saturated) repertoire of well-characterized models will establish the basis to increase therapeutic successes of these drugs in children with solid malignancies. Since these tumours are overall genetically much less complex than their adult counterparts, it is anticipated that it will be easier to identify powerful predictive biomarkers to allow for accurate matching of targets and drugs. To address the significant preclinical gap in identifying promising molecules to fight paediatric cancer, the main objectives for this preclinical platform project are to:

• Establish a representative collection of patient-derived in vitro and in vivo models (~400) as well as genetic mouse models of the most common paediatric solid high-risk entities including a significant proportion of models from relapses, and liquid tumours, including AML, ALL and Burkitt’s lymphoma.
• Molecularly characterize and to quality-assess the models as well as the matching primary tumour samples and germline controls with state-of-the-art molecular diagnostic tools.
• enable regulatory filings in the EU through the development of comprehensive preclinical data packages necessary to move drugs into clinical trials for children with cancer.
• Prioritize paediatric drug development using existing collections of molecular data for systematic target reports, followed by in vivo drug testing in faithful disease models. In vivo drug testing will also include at least three standards-of care regimens for all models.
• Build an international consensus on preclinical data packages for paediatric cancer to enable clinical development.
• Identify suitable biomarkers for future clinical stratification.

Ultimately, the establishment of the sustainable and commercially viable ITCC-P4 will overcome a long-standing gap by enabling thorough molecular characterization of high-risk paediatric malignancies coupled with standardized preclinical testing procedures and will thus greatly expedite the development of more precise and efficacious drugs.
Considerable progress was made in 2022 despite COVID-19 and excellent cooperation continues between academia and EFPIA. In terms of digital communication, the ITCC-P4 website ( is consistently being updated and the number of connections continues to grow in LinkedIn. By the end of 2022 we had 372 fully established patient derived xenograft (PDX) models generated from tumors from 354 patients. Most of the models are available at the testing sites for drug testing, while the remaining are expected to available by the end of Q2 2023. Another 85 models are in early passages in mice. Of the 372 established models, 351 have been fully molecularly characterized, together with the matching patient tumours and blood. Molecular characterization of the remaining models is expected by the end of Q2 2023. At Bayer, imaging proof-of-concept was performed on tumour cell derived brain tumour models, which led to the use of luciferase imaging for in vivo response assessment. At Roche, humanization of rhabdomyosarcoma models was initiated and is ongoing. Regarding in vitro organoid model development, neuroblastoma organoids and models from several other solid tumours were established, while medulloblastoma organoid establishment remained challenging. Based on funding from new EFPIA partners, this activity is extended to cover more common entities to generate up to 100 PDX-derived organoid models. Drug testing in PDX models and in organoids continues (at the PMC) and the results will be compared to in vivo efficacy testing in the PDX models from which the organoids were derived (so-called “Mirror Project”). Information technology advances have continued as evidenced by an enhanced and evolving mouse tumour barcoding system and continued development of the R2 platform ( To support selection, prioritization and planning of targeted molecule efficacy testing, the methodology required for the determination of “target actionability” was established and the first three manuscripts were accepted for publication with an additional three target actionability manuscripts underway. As part of our outreach to the greater paediatric community, we had presentations at various international meetings, mostly virtual due to the pandemic. A white paper following from the multi-stakeholder meeting in Amsterdam in September 2018 was published in Molecular Cancer Therapeutics in August 2021 and became available open access in 2022. This document, the first of its kind for global paediatric research, also served as a basis for a guidance document to be submitted shortly to regulatory authorities for qualification of the process to improve prioritization and effectiveness of drug development for children and adolescents with cancer. Numerous disclosures from the Leadership Team were given across the globe as part of our ongoing effort to inform the worldwide paediatric community of the development and importance of ITCC-P4. Finally, WP7 discussions are way and reflect the rapidly changing pediatric research and regulatory environment. The market sizing was performed and considered the changes in the regulatory environment that will generate an increased need for preclinical testing of anticancer drugs on pediatric tumour models. Two scenarios have been explored in depth for the sustainable platform with the “one-stop shop” model selected by the General Assembly. The business model has been defined and in 2022 a decision was made to form a non-profit gGmbH headquartered in Heidelberg Germany to secure sustainability, with incorporation planned by the end of Q3, 2023.
In addition to the rapid generation of PDX models, where we expect to reach the aim of 400 established models towards the end of the funding period, we were successful in attracting five additional EFPIA (JnJ, Astra Zeneca, Amgen, Servier, Sanofi) partners bringing in cash and in-kind contributions This addition has enabled the inclusion of additional organoid models, notably leukemias and lymphomas and rarer tumor entities, the systematic in vivo testing of several combinations per model and framing the legal aspects of the gGmbH. International visibility has been astonishing as evidenced by invitations to numerous major cancer meetings. The final arbitrage on the business model for the sustainable platform reached a final validation during the 2022 General Assembly. The business case, including the economic assessment of use of the platform by external commercial entities and academic researchers will be further developed in 2023.