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Immune-Image: Specific Imaging of Immune Cell Dynamics Using Novel Tracer Strategies

Periodic Reporting for period 1 - Immune-Image (Immune-Image: Specific Imaging of Immune Cell Dynamics Using Novel Tracer Strategies)

Reporting period: 2019-10-01 to 2020-09-30

Immune-Image aims to develop new imaging technologies to study the effects of modern immune therapies in cancer and inflammation patients (Figure A), which are very successful but unfortunately only in a subset of patients. Our research should lead to new technologies where we can use Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Optical Imaging (OI) to assess if an immune therapy is successful for an individual patient and, even better, to predict if an immune therapy will be effective. If we understand why patients do not respond to immune therapy, we could also design new drugs that will benefit these patients. Imaging is optimally suited for this purpose because a highly sensitive, whole body signal will be measured and the results will be complementary to cellular biology measurements on biopsies.
22 partner institutions work closely together to achieve this overall objective. The work program is divided in 5 scientific and 2 supportive work packages (WP) (Figure B). WP2 aims to standardize the analysis of imaging data. New compounds are synthesized and labelled in WP3, in WP4 these new imaging probes are tested in laboratory animals to provide a proof of concept and in WP5 the best ones are investigated in human disease related animal models. The best new imaging probes will be investigated in WP6, where several small clinical trials will be executed with imaging probes that are ready for human use in addition to new imaging probes. WP1 supports the project management, sustainability of newly developed imaging techniques, communication and dissemination of results. WP7 provides the ethical monitoring for executing pre-clinical and clinical studies.
WP1 drafted the dissemination and communication plan, made a first basis for the sustainability and set up the project organization and governance.

WP2 laid the basis of the Immune-Image data management plan, the establishment of the legal boundary conditions for data sharing, and the selection of the software tools to be used. An accreditation program for image acquisition was set-up and activities include the Imiomics platform developed by one of the Immune-Image SME partners, Antaros.

WP3 First sets of nanobodies targeting human CD8β and CD69 were generated and are currently being characterized extensively in vitro. The first generations of a small molecule and nanobody S100A9 PET tracer were produced, as well as fluorescent labelled PD-L1 antibody. Radiolabelling procedures were installed for immune cells and for CD4 and CD8 tracers.

WP4 determined the ideal set of multi-modality molecular imaging for immune cell tracking. Multimodal whole-body PET/MRI and PET/CT are optimal tools for quantitative whole-body cell tracking studies due to the superior temporal and spatial resolution and high sensitivity of PET. In addition, WP4 successfully established murine IMID and tumor models as well as humanized IMID and tumor models. Models for in vivo cross validation were also successfully established. Progress was made towards establishing imaging protocols for the already available immunotracers.

WP5 investigated the impact of immune therapeutic interventions in various disease models in a longitudinal manner with already existing immune tracers and multi-modal imaging technologies. Moreover, to enable cross-validation, Jurkat cells were successfully transduced with Oatp1- and NIS-expressing constructs.

The combined results of WP4 and 5 so far demonstrate the initial building of the proposed imaging platform to allow in vivo imaging of immunomodulatory therapies in cancer and IMIDs.
WP6 drafted or already submitted the clinical trial protocols and worked extensively on making the sites ready for execution of the clinical studies across sites.

WP7 assessed the relevant ethics requirement for research activities at all partners.
It is too early within the project to report about actual results of the project that have societal / economic impact. The overall progress beyond the state of art will be:

Impact on advancing the field of immune cell imaging
1. Immune-Image will deliver a systematic immunotracer generation platform and ensure that the platform endures beyond Immune-Image.
2. Ready-to-use set of validated PET and OI tracers will be produced. Additionally, MRI approaches to assess immunotherapy will be developed.
3. Immune-Image will produce regulatory accepted standardised protocols with validated immune-imaging approaches.

Advancing clinical and healthcare practice, improving European citizens' health and wellbeing, and making these sustainable
Immune-Image will provide insights into the immunological status of individual patients, which will lead to prediction of response to therapeutic interventions and provide insights into individual therapy responses. The patient will benefit with optimised therapies, increased safety and prevention of unnecessary side effects.

Boost & optimise drug discovery
The immunotracers resulting from Immune-Image will find immediate application in clinical trials, especially phase I and II. There, the immunotracers will be used to visualise and quantify the impact of immunotherapy on specific targets and immunological pathways, thereby reducing ambiguity in the evaluation of immunotherapy efficacy. This will lead to a reduction in the duration and costs of drug development (shorter time-to-market and thus more efficient utilisation of patent/Intellectual property (IP) protection) and attract clinical research of pharmaceutical companies with new immune therapies in Europe.

Impact on basic & translational research
We envision Immune-Image will generate a number of academic demonstration studies, which will lead to opportunities for the development of novel therapeutic interventions. The results of Immune-Image will enable and facilitate R&D activities relevant to other diseases that have an immunological component. Finally, within Immune-Image new scientists in the field will be trained, e.g. PhD students and post-docs, who will drive future research.

Strengthening competitiveness and industrial leadership and addressing specific societal challenges
1. The immunotracer development platform will be used for addressing additional immune system-driven healthcare challenges. This will result in the creation of new jobs and attract additional private investments, e.g. in spin-off companies form academic institutes involved in Immune-Image.
2. Immune-Image will facilitate trans-disciplinary and trans-sectoral collaboration and will boost the development of appropriate business models and generate the desired economic and employment impact at a global level.
3. Support European industrial leadership to successfully compete in the immunotherapy market worldwide .
4. We will actively reach out to European SMEs that focus on immunotherapy drug development to involve them within Immune-Image. We will train them about Immune-Image technologies and transfer those to them at proper conditions.
5. Support economic growth of industry by reducing unnecessary costs. For example, visualisation and quantification of the impact of therapy on specific sites and pathways is expected to decrease ambiguity in the evaluation of treatment efficacy in early stage clinical trials.
6. Increase awareness of the benefits that molecular imaging with immunotracers can create for patients and for all EU citizens.
Figure B: Overview on interactions between all work packages within Immune-Image.
Figure A: Scheme of the sustainable and flexible Immune-Image platform.