Periodic Reporting for period 7 - ITCC-P4 (ITCC Pediatric Preclinical POC Platform – Sofia ref.: 116064)
Periodo di rendicontazione: 2023-01-01 al 2023-12-31
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 facts 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 were 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 and liquid tumours, including AML, ALL and Burkitt’s lymphoma including a significant proportion of models from relapses.
• 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 and outside 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 also included 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 has helped overcome a long-standing gap by enabling thorough molecular characterization of high-risk paediatric malignancies coupled with standardized preclinical testing procedures and is now anticipated to greatly expedite the development of more precise and efficacious drugs.
• 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 and liquid tumours, including AML, ALL and Burkitt’s lymphoma including a significant proportion of models from relapses.
• 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 and outside 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 also included 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 has helped overcome a long-standing gap by enabling thorough molecular characterization of high-risk paediatric malignancies coupled with standardized preclinical testing procedures and is now anticipated to greatly expedite the development of more precise and efficacious drugs.
ITCC-P4 exceeded its lofty goals in terms of both establishment of validated pediatric tumor models and tumor types, as we were able to include liquid tumors in the final platform. In terms of digital communication, an improved ITCC-P4 website was redeveloped (and rebranded to reflect the formation of the non-for-profit spinout company discussed below (now itccp4.comand the number of connections continues to grow in LinkedIn. By the end of the project we had 465 fully established patient derived xenograft (PDX) models. Of these fully established models, 368 have been fully molecularly characterized, together with the matching patient tumours and blood. 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 and neuroblastoma models was initiated and is ongoing. Regarding in vitro organoid model development, models from more than 100 corresponding PDX models were established including several solid tumor and brain tumor indications. Drug testing in PDX models and in organoids continued (at the PMC) and the results will be compared to in vivo efficacy testing in the PDX models from which the organoids are still being derived (so-called “Mirror Project”). Information technology advances resulted in an evolving mouse tumour barcoding system and significant advances in the R2 platform (https://hgserver1.amc.nl/cgi-bin/r2/main.cgi(si apre in una nuova finestra)) including new functionality, for example, user-friendly interfaces designed to marry genomic data with drug efficacy results. 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 under development by project’s end. As part of our outreach to the greater paediatric community, we had presentations at various international meetings, leading to significant awareness of the platform and participants. 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 an Innovation Task Force (ITF) briefing document that was submitted to the EMA and resulted in ITCC-P4 to be classified as a stakeholder with EMA. 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, through intensive work in WP7 the sustainability platform was successfully incorporated in 2024 in Heidelberg, Germany as a non-for-profit company under German law (ITCC-P4 gGmbH). 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. The ITCC-P4 gGmbH sustainability platform is now operational, and contracting with multiple customers, both from the private and the academic sector. It will be represented at relevant meetings moving forward and the marketing strategy is being launched, in particular through a rebranded company website (https://itccp4.com(si apre in una nuova finestra)) and based on direct recommendations.
In addition to the rapid generation of PDX models, where we reached more than 420 models at the end of the project, we additionally attracted five additional EFPIA (JnJ, Astra Zeneca, Amgen, Servier, Sanofi) partners who provided cash and in-kind contributions that allowed further enhancement of nearly all aspects of the platform including an expansion of tumor model offerings (e.g. leukemias and lymphomas); increased development of organoid models; increased drug testing including drug combinations; major expansion of the R2 informatics platform’s offerings; and, notably, the successful establishment of the sustainability platform as a gGmbH. Ultimately, the societal impact will become apparent through the continuous use of the platform by customers from all across the globe, thus serving the needs of children with cancer.