The aim of this work package is to ensure efficient and effective project management and governance structure definition and implementation to assure that imSAVAR’s objectives are successfully fulfilled. Innovation management will take centre stage by facilitating cohesiveness across the consortium through a high level of interaction to maximise the value of public/private partnerships. In addition, communication beyond the consortium is imperative to drive concertation and collaboration efforts parallel to dissemination campaigns and exploitation of project results and assets. Stakeholder engagement and community building will support development of sustainability strategy and planning through a process of iterative design cycles.
WP2 (Immuno-Oncology Models) focuses on refining, adjusting and developing in vitro (2D/3D) as well as in vivo models for three different immune-oncology modes of action (MoA) with a high medical need for improved nonclinical safety assessment:
- chimeric antigen receptor (CAR) T cells
- bispecific T‑cell engagers (BiTEs)
- immune checkpoint inhibitors (ICIs)
The following immune-related adverse events (irAEs) are in the focus of the WP2 work program:
- cytokine release syndrome
This comprises advanced models and biomarkers that reflect mechanisms (i.e. immune-related adverse outcome pathways, irAOPs) and conditions (e.g. the tumor microenvironment) in order to more accurately predict clinical immune system responses.
The work package “Innovative models for safety assessment of immuno-inflammatory disease therapeutics” is focused on the safety assessment of immuno-inflammatory therapeutics. In this context, new models will be developed or existing models will be refined and standardised. To achieve this we started to look from different sites and approaches
- the definition of ideal models for immuno-inflammatory immune safety assessment;
- the comparative assessment of the performance of human in vitro immune cell assays using healthy vs. specific disease states;
- the development of human immune-competent organotypic and microphysiological immuno-inflammatory disease models; and
- using animal models for the assessment of infection and malignancy risk.
In accordance with the OECD (Organisation for Economic Co-operation and Development) Guidance document and based on extensive literature research, a preliminary immune-related adverse outcome pathways (irAOPs) for the mode of action (MoAs) of recombinant human Interleukin-2 (rhIL-2) was developed as a first case study. These irAOPs cover different aspects of rhIL-2-induced side effects regarding different organs and guide the evidence-based development of methods, assays and biomarkers. The included key events cover two important characteristics, they need to be measurable or observable, and they should be important for the functions for which disruption can be causally linked to the adverse outcome. These irAOPs showed data gaps that will further guide experimental work. The role of microbiota derived short chain fatty acids (SCFAs) as potential regulators of the immune response mediated by CAR T-cells as an immunomodulatory treatment option for cancer will be investigated in a gut-on-chip model. In this iPSC based isogenic gut model, the role of SCFAs as potential biomarkers for the safety and efficacy of a combined CAR T cell / IL-2 therapy is being assessed.
The MoAs of rhIL-2 used in human immune-competent organotypic disease model will be mirrored in an in vivo treatment trial. Consequently, a broad variety of biomarkers from body fluids will be received in this proven disease model. The comparison of different treated groups after viral infection will show absence or presence of an influence of the immune balance.
Work package 4 (WP4) focuses on the development and validation of biomarkers for predicting the risk of observing harmful adverse outcomes in first-in-human (FIH) studies of immunomodulatory therapeutics.
Since human molecular and cellular responses to molecular initiating events of immune-related adverse events are complex, WP4 relies on an unbiased ex-vivo assessment using multi-parametric measurements (longitudinal, single-cell or spatial resolution). With that, WP4 uncovers mechanistic insights of molecular initiating events, key events and key event relationships eventually leading to severe toxicities. New findings are aligned with immune-related Adverse Outcome Pathways (irAOPs), thus guiding development and validation of novel biomarkers. The aim is to develop biomarkers that are measurable and evaluable and can be integrated into safety models in order to
- assess if the model mimics the underlying human biological processes leading to an immune-related adverse outcome as closely as possible;
- assess if the biomarker is reliably predicting the risk of harmful adverse outcomes in FIH studies; and
- support safe starting dose selection for FIH studies.
One focus of Work Package 5 (WP5) is the centralization of all data generated in the project in order to make them available for further analysis. Therefore, a data management platform is set-up to enable secure, scalable, and integrated storage, as well as exploration and sharing of data collected and used in the project. To guarantee data quality and interoperability, data uploaded to the platform will to be curated and standardised according to guidelines developed in the community and related projects. To meet the data protection guidelines and regulations, necessary security, and access control mechanism, including secure communication, heterogeneous security mechanisms, and prevention of re-identification of subjects will be implemented in the data repository site. WP5 also performs data management operation as well as developing a catalogue of datasets and a catalogue of assays and models. In addition, WP5 is responsible for all issues related to biobanking. For this purpose, existing biobank infrastructure can be used, including a biobank management system for the documentation of the collection of biospecimen in the project. Implementation of guidelines for the preanalytical handling, storage and shipping of samples ensure consistently high sample quality. Furthermore, a network of disease domain experts who can provide samples and immune cells will be developed involving the German as well as the European biobank network as an important source of biospecimens.