Periodic Reporting for period 4 - imSAVAR (Immune Safety Avatar: nonclinical mimicking of the immune system effects of immunomodulatory therapies)
Okres sprawozdawczy: 2022-12-01 do 2023-11-30
Toxicities associated with immunomodulatory drugs are often not detected during non-clinical development. This is because existing non-clinical animal and cellular models do not adequately represent the complexity of the of immune system. The imSAVAR objectives are:
- To develop a framework for identification of gaps in immune safety assessment focusing on specific modes of action (MoA)
- To refine existing models, develop new models, and identify pharmacodynamic and toxicologic biomarkers for preclinical assessment of safety
- To establish a platform that combines models with biosample to enable improved immune safety assessments
- To create an immune safety stakeholder community and business models that can extend the vision beyond the funding period.
- To develop a framework for identification of gaps in immune safety assessment focusing on specific modes of action (MoA)
- To refine existing models, develop new models, and identify pharmacodynamic and toxicologic biomarkers for preclinical assessment of safety
- To establish a platform that combines models with biosample to enable improved immune safety assessments
- To create an immune safety stakeholder community and business models that can extend the vision beyond the funding period.
ImSAVAR’s overall approach involves iterative cycles based upon a set of workflows that move from case studies, to models developed with samples from healthy tissues, or non-disease in vivo models, to models that include samples from disease and in vivo disease models. During the fourth year of the project, the consortium has accomplished significant progress in the following WPs:
WP1: continued to facilitate the collaboration between partners by organizing regular meetings as well as the 5th consortium meeting. The Management Board was slightly restructured to rotate members. Additionally, we engaged with our Regulatory and Ethics Board members in a call preceding the consortium meeting. WP1 completed and successfully submitted annual reports to the European Commission and prepared a 4th amendment. The communication strategy was revised in response to comments from the midterm review. Sustainability planning was initiated to ensure continuity beyond EC funding.
Patient stakeholder engagement has been moving forward with two key events that resulted in considering sex differences in new preclinical models, and analysing the results of existing data with the researchers.
WP2: The different immune-related adverse outcome pathways (irAOPs) for the adverse outcome cytokine release syndrome (CRS) developed for CAR-T cells, bispecific T cell engagers (TCEs) and checkpoint inhibitors (CPIs) were harmonized during the first imSAVAR study-a-thon. Disease maps modelling the irAOPs on the MINERVA platform were further refined and biomarkers as well as (in vitro) model systems were assigned to the appropriate key event(s) within the harmonized irAOP. This will be one means of identifying gaps in safety assessment and further guide the model development within imSAVAR.
LabCorp’s autologous BOEC platform, originally established at the Imperial College London, is starting to gain use in different working groups and work packages within imSAVAR as we look towards biomarker discovery of disease pathologies such as CRS.
Efforts towards model optimization continued with the further refinement of the tumor- and vessel-on-chip models, also by including additional donors and readouts.
WP3: The established framework to investigate undesired effects of high- and low-dose IL-2-treatment has been applied and refined. The various immune-related irAOPs for IL-2-therapy into one irAOP for IL-2-mediated toxicities were further harmonized. First steps to harmonize all IL-2-related AOPs developed within imSAVAR have been taken.
Moreover, the different model systems refined and developed based on the elaborated irAOPs are established and/or applied to generate wet-lab data analysing well-known side effects induced by IL-2 immunotherapy. The publication of the joint issue of several manuscripts of imSAVAR partners in one special imSAVAR journal issue was delayed to the lack of reviewers.
WP4 continued to implement biomarker related information into irAOPs, because irAOPs guide the development of non-clinical models for immunomodulatory therapies in imSAVAR. A preprint describing an interactive platform to encode, manage and explore irAOPs is available.
WP4 organized the first imSAVAR study-a-thon to develop an integrated map of CRS induced by various immunotherapies (CAR T cells, BITEs, CPIs) that is accessible via MINERVA. A novel multi-response regression approach allows for biomarker identification with small sample sizes. Time-resolved meta-analysis of T cell populations after non-specific activation identified and verified biomarkers and correlated those to ICANS. Transcriptional states of CAR T cell infusion products were related to ICANS utilizing single-cell SOM expression portraying. WP4 assessed biomarkers in a cross-consortium comparison of non-standard in vitro cytokine release assays, and proceeded with the determination of molecular biomarkers in patient-derived samples.
WP 5 updated the sample metadata template and shared the revised version with stakeholders after a round of workshops that included suggestions and feedback from stakeholders. Moreover, WP 5 created a simplified version of the Data Sharing Agreement (DSA) to ensure it is easily understandable by researchers. Furthermore, a Data Catalogue has been established for imSAVAR, along with DAISY – a system for recording data access activities. Lastly, UNILU has received two datasets from ROCHE and BI.
WP1: continued to facilitate the collaboration between partners by organizing regular meetings as well as the 5th consortium meeting. The Management Board was slightly restructured to rotate members. Additionally, we engaged with our Regulatory and Ethics Board members in a call preceding the consortium meeting. WP1 completed and successfully submitted annual reports to the European Commission and prepared a 4th amendment. The communication strategy was revised in response to comments from the midterm review. Sustainability planning was initiated to ensure continuity beyond EC funding.
Patient stakeholder engagement has been moving forward with two key events that resulted in considering sex differences in new preclinical models, and analysing the results of existing data with the researchers.
WP2: The different immune-related adverse outcome pathways (irAOPs) for the adverse outcome cytokine release syndrome (CRS) developed for CAR-T cells, bispecific T cell engagers (TCEs) and checkpoint inhibitors (CPIs) were harmonized during the first imSAVAR study-a-thon. Disease maps modelling the irAOPs on the MINERVA platform were further refined and biomarkers as well as (in vitro) model systems were assigned to the appropriate key event(s) within the harmonized irAOP. This will be one means of identifying gaps in safety assessment and further guide the model development within imSAVAR.
LabCorp’s autologous BOEC platform, originally established at the Imperial College London, is starting to gain use in different working groups and work packages within imSAVAR as we look towards biomarker discovery of disease pathologies such as CRS.
Efforts towards model optimization continued with the further refinement of the tumor- and vessel-on-chip models, also by including additional donors and readouts.
WP3: The established framework to investigate undesired effects of high- and low-dose IL-2-treatment has been applied and refined. The various immune-related irAOPs for IL-2-therapy into one irAOP for IL-2-mediated toxicities were further harmonized. First steps to harmonize all IL-2-related AOPs developed within imSAVAR have been taken.
Moreover, the different model systems refined and developed based on the elaborated irAOPs are established and/or applied to generate wet-lab data analysing well-known side effects induced by IL-2 immunotherapy. The publication of the joint issue of several manuscripts of imSAVAR partners in one special imSAVAR journal issue was delayed to the lack of reviewers.
WP4 continued to implement biomarker related information into irAOPs, because irAOPs guide the development of non-clinical models for immunomodulatory therapies in imSAVAR. A preprint describing an interactive platform to encode, manage and explore irAOPs is available.
WP4 organized the first imSAVAR study-a-thon to develop an integrated map of CRS induced by various immunotherapies (CAR T cells, BITEs, CPIs) that is accessible via MINERVA. A novel multi-response regression approach allows for biomarker identification with small sample sizes. Time-resolved meta-analysis of T cell populations after non-specific activation identified and verified biomarkers and correlated those to ICANS. Transcriptional states of CAR T cell infusion products were related to ICANS utilizing single-cell SOM expression portraying. WP4 assessed biomarkers in a cross-consortium comparison of non-standard in vitro cytokine release assays, and proceeded with the determination of molecular biomarkers in patient-derived samples.
WP 5 updated the sample metadata template and shared the revised version with stakeholders after a round of workshops that included suggestions and feedback from stakeholders. Moreover, WP 5 created a simplified version of the Data Sharing Agreement (DSA) to ensure it is easily understandable by researchers. Furthermore, a Data Catalogue has been established for imSAVAR, along with DAISY – a system for recording data access activities. Lastly, UNILU has received two datasets from ROCHE and BI.
This project will establish a platform of processes for developing nonclinical assessment strategies and models that represent the complexity of diseases and have been shown to be predictive of immune related adverse events. The generation of integrated nonclinical overviews for Investigational New Drug and clinical trial applications will be based upon the imSAVAR standard, making the process much more efficient. The platform will continue after the funding period driven by a stakeholder community for developing new assessment strategies and supporting the implementation of existing ones.
One expected result is the provision of new tools and models to enable a better understanding of the inherent safety risks of immunomodulatory therapeutics with regards to more efficient drug development, better mechanistic and safety insights and new market for tools and diagnostics. This will help different stakeholder groups like pharma, regulators, researchers and SMEs.
Another expected result is the improvement of drug development processes and regulatory assessments for immunomodulatory therapeutics through the characterisation of innovative immunobiology models and biomarkers, an important aspect for regulators, Pharma and society with for better immunosafety assessment coordination.
Through collaboration with the patient stakeholder community, we will enhance translational safety assessment of innovative immunomodulatory therapeutics through a better understanding what is important for patients with respect to disease and treatment.
Limitations in the translatability of non-clinical test system to patients will be better defined, which will enable the most appropriate and efficient combinations of test systems to be used in future safety assessment and contributing to 3Rs. This will help researchers develop more impactful models. Furthermore, pharma will experience an increased efficiency in immuno-safety assessment and society will be less reliant on animal testing.
Lastly, a network of centres for providing samples will be established. This system will allow anyone to follow a procedure for requesting samples online. The available samples will be suitable for use in immunosafety models that reflect a broad array of disease domains.
One expected result is the provision of new tools and models to enable a better understanding of the inherent safety risks of immunomodulatory therapeutics with regards to more efficient drug development, better mechanistic and safety insights and new market for tools and diagnostics. This will help different stakeholder groups like pharma, regulators, researchers and SMEs.
Another expected result is the improvement of drug development processes and regulatory assessments for immunomodulatory therapeutics through the characterisation of innovative immunobiology models and biomarkers, an important aspect for regulators, Pharma and society with for better immunosafety assessment coordination.
Through collaboration with the patient stakeholder community, we will enhance translational safety assessment of innovative immunomodulatory therapeutics through a better understanding what is important for patients with respect to disease and treatment.
Limitations in the translatability of non-clinical test system to patients will be better defined, which will enable the most appropriate and efficient combinations of test systems to be used in future safety assessment and contributing to 3Rs. This will help researchers develop more impactful models. Furthermore, pharma will experience an increased efficiency in immuno-safety assessment and society will be less reliant on animal testing.
Lastly, a network of centres for providing samples will be established. This system will allow anyone to follow a procedure for requesting samples online. The available samples will be suitable for use in immunosafety models that reflect a broad array of disease domains.