Periodic Reporting for period 2 - imSAVAR (Immune Safety Avatar: nonclinical mimicking of the immune system effects of immunomodulatory therapies)
Reporting period: 2020-12-01 to 2021-11-30
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 objective in imSAVAR is:
- 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 second year of the project despite the disruption caused by the pandemic, the consortium has continued to establish a strong communication structure and has accomplished significant progress in 2021 in the following WPs:
WP1 organized two science days on 25-26 May 2021, which were held virtually due to the continuing pandemic situation. The Consortium Meeting also took place on 02 June 2021 via video call. In addition, the imSAVAR meeting structure was adapted for organizational reasons. To strengthen the dissemination of imSAVAR results and achievements, a communication and dissemination group was created. An Ethics and Regulatory Advisory Board was also established.
WP2 partners further refined the framework for identification of gaps in safety assessment of immuno-oncology therapies, which will be implemented into an interactive platform. CAR T cells generated from healthy donors were tested in different assays and advanced models available within the consortium. Further, new and improved advanced test systems, with a special focus on autologous and patient-specific test systems, were developed that can be used to evaluate the safety of different immunotherapeutic modalities. Furthermore, a scientific study to identify molecular biomarkers in patients undergoing CAR-T cell therapy has been initiated together with partner Fraunhofer IZI (WP4).
Work Package 3 mainly focused on further refinement of IL-2-mediated immune-related adverse outcome pathways (irAOPs) in four different organs. These irAOPs build the base for testing, adaption and refinement of different test systems regarding their ability to reflect and predict a putative clinical outcome. To present the results to a bigger audience, a stakeholder workshop with the focus on irAOPs has been organized together with WP1. In close cooperation with WP4 the complexity of the irAOPs has been brought together in a machine-readable modelling tool. In this context, new models based on 3D and organ-on-a-chip technology are under development within WP3.3. In order to round up the picture, the transfer to in vivo models has been carefully planned in WP3.4.
WP4 organized a webinar on cytokine-release assays and their integration into non-clinical safety models. Additionally, we further improved vessel-on-a-chip models to examine cytokine release and established workflows for single cell and spatial sequencing for immune cell profiling in non-clinical models.The MINERVA-tool for machine-readable modelling of irAOPs has been established and we prepared a conceptional view on integrating of biomarkers into irAOPs ensuring early regulatory assessment of biomarkers. We set up a research study to determine the mode of action (MoA) of CAR T cells in patients by identifying molecular biomarkers that can be assessed in in vitro models to predict irAEs. Additionally, we finished literature reviews of biomarkers and studies relevant to imSAVAR to establish a data catalogue to disentangle molecular mechanisms of irAOPs.
WP5 developed a sample metadata template. The template collects information such as unique ID (imSAVAR ID), date of sampling, storage medium, storage temperature, etc. using controlled terminology, and is used to import data about samples into the data and knowledge integration IT platform. The use of this template ensures a uniform wide range use for all biospecimens collected. This includes the use for future investigations and questions that are not yet foreseeable and the use for genetic studies. Furthermore, in order to sensitize all partners to sample quality, WP5 partners started to develop a biobanking guideline for the handling of biospecimens (sample collection, processing, labelling, storage, shipping and documentation) to ensure a consistent high quality of biosamples within the project.
WP1 organized two science days on 25-26 May 2021, which were held virtually due to the continuing pandemic situation. The Consortium Meeting also took place on 02 June 2021 via video call. In addition, the imSAVAR meeting structure was adapted for organizational reasons. To strengthen the dissemination of imSAVAR results and achievements, a communication and dissemination group was created. An Ethics and Regulatory Advisory Board was also established.
WP2 partners further refined the framework for identification of gaps in safety assessment of immuno-oncology therapies, which will be implemented into an interactive platform. CAR T cells generated from healthy donors were tested in different assays and advanced models available within the consortium. Further, new and improved advanced test systems, with a special focus on autologous and patient-specific test systems, were developed that can be used to evaluate the safety of different immunotherapeutic modalities. Furthermore, a scientific study to identify molecular biomarkers in patients undergoing CAR-T cell therapy has been initiated together with partner Fraunhofer IZI (WP4).
Work Package 3 mainly focused on further refinement of IL-2-mediated immune-related adverse outcome pathways (irAOPs) in four different organs. These irAOPs build the base for testing, adaption and refinement of different test systems regarding their ability to reflect and predict a putative clinical outcome. To present the results to a bigger audience, a stakeholder workshop with the focus on irAOPs has been organized together with WP1. In close cooperation with WP4 the complexity of the irAOPs has been brought together in a machine-readable modelling tool. In this context, new models based on 3D and organ-on-a-chip technology are under development within WP3.3. In order to round up the picture, the transfer to in vivo models has been carefully planned in WP3.4.
WP4 organized a webinar on cytokine-release assays and their integration into non-clinical safety models. Additionally, we further improved vessel-on-a-chip models to examine cytokine release and established workflows for single cell and spatial sequencing for immune cell profiling in non-clinical models.The MINERVA-tool for machine-readable modelling of irAOPs has been established and we prepared a conceptional view on integrating of biomarkers into irAOPs ensuring early regulatory assessment of biomarkers. We set up a research study to determine the mode of action (MoA) of CAR T cells in patients by identifying molecular biomarkers that can be assessed in in vitro models to predict irAEs. Additionally, we finished literature reviews of biomarkers and studies relevant to imSAVAR to establish a data catalogue to disentangle molecular mechanisms of irAOPs.
WP5 developed a sample metadata template. The template collects information such as unique ID (imSAVAR ID), date of sampling, storage medium, storage temperature, etc. using controlled terminology, and is used to import data about samples into the data and knowledge integration IT platform. The use of this template ensures a uniform wide range use for all biospecimens collected. This includes the use for future investigations and questions that are not yet foreseeable and the use for genetic studies. Furthermore, in order to sensitize all partners to sample quality, WP5 partners started to develop a biobanking guideline for the handling of biospecimens (sample collection, processing, labelling, storage, shipping and documentation) to ensure a consistent high quality of biosamples within the project.
At the end of this project there will be a platform of processes for developing non-clinical assessment strategies, models that represent the complexity of diseases and have been shown to be predictive of immune related adverse events The generation of integrated non-clinical 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. This will be important for regulators, Pharma and society with regards to a better immunosafety assessment coordination.
The diverse interactions with patient stakeholder community that started in 2021 will make it possible for the consortium to enhance translational safety assessment of innovative immunomodulatory therapeutics through a better understanding of what is important for patients with respect to disease and treatment.
Thirdly there will be a better definition of limitations in the translatability of non-clinical test system to patients 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 in developing 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. This will be important for regulators, Pharma and society with regards to a better immunosafety assessment coordination.
The diverse interactions with patient stakeholder community that started in 2021 will make it possible for the consortium to enhance translational safety assessment of innovative immunomodulatory therapeutics through a better understanding of what is important for patients with respect to disease and treatment.
Thirdly there will be a better definition of limitations in the translatability of non-clinical test system to patients 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 in developing 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.