An integrated approach to restore tolerance in autoimmune disease

Project Information

TOLERATE

Grant agreement ID: 101072729

DOI

10.3030/101072729

EC signature date 1 June 2022

Start date 1 October 2022

End date 30 September 2026

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 2 109 650,40

Coordinated by

KATHOLIEKE UNIVERSITEIT LEUVEN
Belgium

Periodic Reporting for period 1 - TOLERATE (An integrated approach to restore tolerance in autoimmune disease)

Reporting period: 2022-10-01 to 2024-09-30

Summary of the context and overall objectives of the project

The TOLERATE training network aims to equip Doctoral Candidates (DCs) with the skills to develop innovative strategies for treating autoimmune diseases. This includes identifying the most promising strategies or combinations, setting up clinical trials with diagnostics for patient selection and trial enrichment, and creating a roadmap to bring new therapeutic agents to market. This will be achieved in a highly interdisciplinary and intersectoral environment.
Interdisciplinarity allows for the introduction of innovative antigen-specific immune therapies, such as Chimeric Antigen Receptor (CAR)-T cell therapies originally developed for cancer, into the realm of autoimmune diseases. It also enables the application of nanotechnology and tolerogenic vaccines to re-establish immune tolerance in autoimmune diseases. The collaboration between academia and industry provides a platform for in-depth preclinical studies focused on the development and future commercialization of novel therapies. Clinical key opinion leaders in the consortium will ensure that the therapies developed in TOLERATE reach the clinic.
A thorough understanding of the long-term consequences of living with an autoimmune disease is crucial for designing new therapies. Since many autoimmune diseases are rare, establishing international uniform databases and biobanks is essential to understand the long-term pathophysiology of these diseases and to ensure the optimal use of new therapies. The presence of a renowned autoimmune disease reference center will help address this unmet need. The autoimmune disease immune-mediated thrombotic thrombocytopenic purpura (iTTP), characterized by a single self-antigen, will be central to TOLERATE, with academic and clinical experts who are world leaders in this field.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

This DN has recruited 8 Doctoral Candidates (DCs) who have undertaken a range of training activities. This has included research-focued training and includes consortium wide training, bespoke personalised training packages and operational training, entrepreneurial, management and presentations skills and ethics training. Their research is conducted across five research work packages:
WP1 Innovative CAR-/TCR-engineered T cell therapies
WP2 Innovative therapies to restore antigen specific tolerance
WP3 ADAMTS13 (targeted) clearance
WP4 Long-term follow-up of autoimmune diseases
WP5 Identify the most promising (combined) innovative therapies
Each of the DCs has an individual, personalised research project joint supervised by a multi-disciplinary cross-sector team of at least two supervisors. Each project has been designed to take full advantage of expertise, methodology and technology available within the consortium.

DC1 gathered iTTP patient data, focusing on patients who had been treated with innovative agents like obinutuzumab and daratumumab. After compiling the data and conducting statistical analyses their findings were published. DC2 and DC3 have successfully developed innovative CAR T cells, TMs, and target cells for CAR T cell therapy and have proven their efficacy in in vitro cytotoxicity assays. DC4 isolated Peripheral Blood Mononuclear Cells (PBMCs) and sorted T CD4+ cells using FACS from healthy donors to next stimulate PBMCs with ADAMTS13-derived peptides and identify a T-cell receptor (TCR). DC5 has been constructing tolerogenic vaccines by generating fusion proteins of ADAMTS13 with relevant proteins, aiming to create tolerogenic vaccines. Additionally, DC5 selected an ADAMTS13 CUB2 domain-derived peptide, and coupled it with the TAT cell-penetrating peptide to target red blood cells (RBCs) and harness their tolerogenic properties. DC6 successfully designed and scaled up the manufacturing of PS-liposomes encapsulating a single ADAMTS13-derived peptide. DC7 made progressed in understanding the cell types and receptors involved in the clearance of ADAMTS13. Furthermore, DC7 identified a new role for a specific receptor in regulating the physiological clearance of ADAMTS13 in vivo. DC8 isolated and cryopreserved PBMCs from iTTP patients, including those with relapses and those in remission, and sent the samples to DC5 and DC6. Additionally, a database was established at SMW, according to the standardized follow-up protocol set up in Paris, to track iTTP patients with index events and available samples prior to these events. Finally, with the collective efforts of all DCs and close collaboration, standardized clinical databases for TTP and ADAMTS13 measurements were established during their 5-week clinical training in Paris, marking a significant milestone in the field.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

If the novel therapies developed in TOLERATE show the potential for clinical development, additional works needs to be done to make the therapies ready for clinical development: gap analysis, market analysis, search for new IP opportunities, apply for a rare disease designation file, setup a business plan, look for investors, etc.

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