Periodic Reporting for period 5 - imSAVAR (Immune Safety Avatar: nonclinical mimicking of the immune system effects of immunomodulatory therapies)
Reporting period: 2023-12-01 to 2024-11-30
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 fifth year of the project, the consortium has accomplished significant progress:
WP1 focused on project management and innovation, successfully finalizing the IMI Annual Activity Report and gaining approval for the fourth periodic report. The Project Management Office (PMO) organized a study-a-thon and hosted a hybrid consortium meeting in November 2024. Regular meetings fostered innovation management, emphasizing patient sample usage, model validation, and community building around immune-related adverse outcome pathways (irAOPs). Stakeholder engagement led to drafting a white paper on irAOPs and enhanced dissemination efforts, culminating in increased social media engagement and a special issue of the Journal of Immunotoxicology.
WP2 achieved the harmonization of irAOPs for cytokine release syndrome (CRS), integrating this into the MINERVA platform. The consortium submitted two key manuscripts: one detailing the harmonized CRS irAOP and another on cytokine release assays in immunotherapy. Lund developed a BOEC:PBMC co-culture model to predict CRS risk in patients treated with checkpoint inhibitors. A cross-consortium study aims to correlate donor phenotypes with CRS susceptibility using in vitro cytokine release assays. The breast-cancer-on-chip model was refined to enhance CAR-T efficacy and safety testing, while upgraded vessel-on-chip models provided insights into inflammatory cell recruitment, vascular leakage and coagulopathies. Biomarkers linked to cytopenias were identified in CAR-T patients, with ongoing validation supported by extensive patient data collection. CPI studies indicated no hepatotoxicity in co-culture models, prompting further research into long-term effects.
WP3 refined the framework for investigating side effects of high- and low-dose IL-2 treatments. Regular meetings facilitated effective knowledge transfer and data discussions. Results from in vitro, ex vivo, in vivo, and microphysiological models were published in a special issue of the Journal of Immunotoxicology. The harmonization of irAOPs for IL-2-mediated skin rash, hepatotoxicity, and vascular leakage was completed, with efforts to transfer these findings to other drugs for agnostic irAOP development. Refined models, including co-cultures of tissue-resident and immune cells, generated wet-lab data on IL-2 side effects. Ongoing model optimization and biobank establishment for relevant samples are in progress, although sample availability for high-throughput immune safety assessments remains limited.
WP4 established a framework for integrating biomarker development into the irAOPs concept, essential for nonclinical models in immunomodulatory therapies. Existing OECD guidelines regarding biomarkers were found lacking, prompting ongoing efforts in this area. Key developments included the publication of an irAOP for CAR-T cells and a model for CRS. Collaborative work with EFPIA partners focused on creating standardized protocols for biomarker assessment. Progress on the CAR-T cell atlas advanced nonclinical therapy development. A cross-consortium study was initiated to ensure the safe transition of immunomodulatory drugs to human trials. The MINERVA platform was effectively utilized for mapping irAOPs, enhancing the understanding of immune-related adverse events. Significant strides were made in identifying biomarkers linked to CRS through patient data analysis, with ongoing refinement of guidelines for biomarker development.
WP5 refined the Data Catalogue and the DAISY system for documenting data access activities. Workshops, both online and in-person, clarified questions about Data Information Sheets (DISHs) and data uploads to UNILU. The contract with the hepatocyte biobank in Leipzig was extended to include hepatic immune cells for WP3. Additionally, well-characterized lung specimens for precision cut lung slices (PCLS) were provided, yielding samples from 13 disease-free and 17 end-stage fibrotic lungs, although the availability of suitable end-stage samples slightly decreased. A comprehensive Catalogue of Assays and Models was delivered, consolidating experimental tools for all stakeholders involved.
WP1 focused on project management and innovation, successfully finalizing the IMI Annual Activity Report and gaining approval for the fourth periodic report. The Project Management Office (PMO) organized a study-a-thon and hosted a hybrid consortium meeting in November 2024. Regular meetings fostered innovation management, emphasizing patient sample usage, model validation, and community building around immune-related adverse outcome pathways (irAOPs). Stakeholder engagement led to drafting a white paper on irAOPs and enhanced dissemination efforts, culminating in increased social media engagement and a special issue of the Journal of Immunotoxicology.
WP2 achieved the harmonization of irAOPs for cytokine release syndrome (CRS), integrating this into the MINERVA platform. The consortium submitted two key manuscripts: one detailing the harmonized CRS irAOP and another on cytokine release assays in immunotherapy. Lund developed a BOEC:PBMC co-culture model to predict CRS risk in patients treated with checkpoint inhibitors. A cross-consortium study aims to correlate donor phenotypes with CRS susceptibility using in vitro cytokine release assays. The breast-cancer-on-chip model was refined to enhance CAR-T efficacy and safety testing, while upgraded vessel-on-chip models provided insights into inflammatory cell recruitment, vascular leakage and coagulopathies. Biomarkers linked to cytopenias were identified in CAR-T patients, with ongoing validation supported by extensive patient data collection. CPI studies indicated no hepatotoxicity in co-culture models, prompting further research into long-term effects.
WP3 refined the framework for investigating side effects of high- and low-dose IL-2 treatments. Regular meetings facilitated effective knowledge transfer and data discussions. Results from in vitro, ex vivo, in vivo, and microphysiological models were published in a special issue of the Journal of Immunotoxicology. The harmonization of irAOPs for IL-2-mediated skin rash, hepatotoxicity, and vascular leakage was completed, with efforts to transfer these findings to other drugs for agnostic irAOP development. Refined models, including co-cultures of tissue-resident and immune cells, generated wet-lab data on IL-2 side effects. Ongoing model optimization and biobank establishment for relevant samples are in progress, although sample availability for high-throughput immune safety assessments remains limited.
WP4 established a framework for integrating biomarker development into the irAOPs concept, essential for nonclinical models in immunomodulatory therapies. Existing OECD guidelines regarding biomarkers were found lacking, prompting ongoing efforts in this area. Key developments included the publication of an irAOP for CAR-T cells and a model for CRS. Collaborative work with EFPIA partners focused on creating standardized protocols for biomarker assessment. Progress on the CAR-T cell atlas advanced nonclinical therapy development. A cross-consortium study was initiated to ensure the safe transition of immunomodulatory drugs to human trials. The MINERVA platform was effectively utilized for mapping irAOPs, enhancing the understanding of immune-related adverse events. Significant strides were made in identifying biomarkers linked to CRS through patient data analysis, with ongoing refinement of guidelines for biomarker development.
WP5 refined the Data Catalogue and the DAISY system for documenting data access activities. Workshops, both online and in-person, clarified questions about Data Information Sheets (DISHs) and data uploads to UNILU. The contract with the hepatocyte biobank in Leipzig was extended to include hepatic immune cells for WP3. Additionally, well-characterized lung specimens for precision cut lung slices (PCLS) were provided, yielding samples from 13 disease-free and 17 end-stage fibrotic lungs, although the availability of suitable end-stage samples slightly decreased. A comprehensive Catalogue of Assays and Models was delivered, consolidating experimental tools for all stakeholders involved.
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.