Development and implementation in clinical practice of the allogeneic use of thymus-derived regulatory T cells (thyTreg) as a cell therapy to suppress harmful immune responses

Project Information

Allo-THYTECH

Grant agreement ID: 101028834

DOI

10.3030/101028834

Project closed

EC signature date 24 March 2021

Start date 23 March 2022

End date 12 July 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 172 932,48

EU contribution

€ 172 932,48

Coordinated by

FUNDACION PARA LA INVESTIGACION BIOMEDICA DEL HOSPITAL GREGORIO MARANON
Spain

Periodic Reporting for period 1 - Allo-THYTECH (Development and implementation in clinical practice of the allogeneic use of thymus-derived regulatory T cells (thyTreg) as a cell therapy to suppress harmful immune responses)

Reporting period: 2022-03-23 to 2024-03-22

Summary of the context and overall objectives of the project

The immune system is responsible for defending the body against external threats and preventing the proliferation of tumor cells. However, it can also produce excessive or unwanted responses, leading to inflammatory processes that may cause severe pathologies such as autoimmune diseases, graft rejection, or neurodegenerative disorders. The immunosuppressive drugs commonly used to treat these inflammatory conditions are generally non-specific and can impair all immune responses, including those that protect against infections and cancer.
Given these challenges, alternative strategies are being explored to achieve a more balanced immune response without resorting to broad-spectrum immunosuppressive drugs. Among the most promising strategies is cell therapy, which seeks to restore immune balance. Recent scientific studies have shown that the immune system has intrinsic regulatory mechanisms, particularly through regulatory T cells (Tregs), which help control and reduce inappropriate inflammatory responses. This MSCA project focuses on developing an innovative approach to produce Treg cell therapies and overcoming the limitations of current methods to make Treg cell therapy a viable treatment option.
The potential outcomes of this project could have significant societal impact by offering new therapeutic options for diseases with a high incidence in the population—approximately 4-6% of the European population is estimated to suffer from some autoimmune disorder. Additionally, this cell therapy could serve as an alternative to immunosuppressive drugs, potentially reducing their severe side effects in patients.
Our research is pioneering the use of human Tregs derived from thymic tissue (thyTregs) rather than blood Tregs, which has enabled us to obtain a larger number of higher-quality cells. The thymic tissue used in our research is typically discarded during pediatric cardiac surgeries, allowing us to prepare and cryopreserve hundreds of therapeutic doses of thyTregs. This "ready-to-use" therapy could be administered to patients other than the original donor, enabling allogeneic treatment. The primary objective of this project was to characterize these thyTregs, optimize protocols for their production and cryopreservation, and validate the feasibility and safety of this approach by initiating a first-in-human clinical trial using allogeneic thyTreg therapy.
The project has provided valuable insights into the phenotype and functionality of thyTreg cells, demonstrating their potential as an "off-the-shelf" therapy. Our results have also highlighted the advantages and distinctive properties of thyTregs compared to Tregs obtained from other sources.

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

We successfully achieved our project objectives, confirming the initial hypothesis and addressing the questions posed by our research. Utilizing thymic tissue as a source of Treg cells for therapeutic purposes renders a product with high purity and cell count. These thyTregs exhibit improved features and functionality compared to Tregs obtained from peripheral or cord blood. Notably, thyTregs possess a phenotype that reduces their recognition by the immune system of a different person, making it possible to use cells from a single donor in multiple recipients without requiring compatibility. This means thyTregs can be administered to any individual and remain "invisible" to the recipient's immune system, preventing the rejection of the cells and rendering the therapy effective. This aspect is critical, as it enables the production of a "ready-to-use" therapy of cryopreserved thyTregs that can be administered to a wide range of patients, reducing costs and logistical challenges.
We have also engaged in public dissemination efforts by organizing outreach activities to raise awareness about the significance of this research, instill hope in patients suffering from these serious diseases and their families, and promote scientific careers among young people. To further exploit the project results, we are exploring the development of new patents related to the allogeneic use of thyTregs, supported by our findings. Additionally, the beneficiary has co-founded a start-up focused on developing thyTreg therapy to bring the product to market and patients.

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)

This project and its results represent a proof of concept for an innovative approach to developing Treg cell therapies, adopting a unique strategy that overcomes many constraints associated with conventional protocols.
High Clinical Impact: The success of this project is crucial for demonstrating the efficacy of allogeneic Treg cell therapy in human immune-mediated diseases. Restoring immune homeostasis through thyTreg immunotherapy could not only resolve the inflammatory processes underlying these diseases but also allow the recovery of patients' natural immune tolerance. This could reduce or eliminate the need for immunosuppressive or biological treatments, establishing a new paradigm in clinical management. Furthermore, the development of a "ready-to-use" cell therapy that does not require individualized autologous production for each patient and can be used without HLA compatibility offers significant potential for treating a wide range of immunity-related diseases, such as autoimmune disorders, which affect millions of people. This strategy, where a production center provides hundreds of doses, would facilitate the broader adoption of the therapy by healthcare institutions.
High Scientific Impact: Over the past decade, the innovative nature and importance of this research line have led to the publication of its results in highly recognized scientific journals. The scientific impact of a new clinical application of these results is expected to be even greater, given the pioneering nature of the project, potentially leading to high-impact publications. The multidisciplinary nature of the project, addressing immunological aspects, immune-mediated processes, and improvements in patients' quality of life, also suggests a high degree of dissemination at scientific congresses.
High Economic Impact: The significance of this trial extends beyond clinical implications to include the costs to national health systems and the impact of innovation on national economic growth. In 2023, the average annual cost of immunosuppressive therapies and biological drugs for patients affected by these diseases was approximately €7,000 per patient, excluding costs related to side effects, and these treatments must be administered chronically. In contrast, the estimated cost of thyTreg therapy involves a single payment of around €13,000 per processed thymus, from which dozens of therapeutic doses could be generated for allogeneic use, potentially treating multiple adult patients. Preliminary evidence from our autologous trial suggests that the benefits of a single dose of thyTreg can last for several years. Therefore, Treg cell immunotherapy for patients with autoimmune processes could become a cost-effective practice for national health systems. Additionally, as a pioneering global project, the technology developed here is likely to have commercial potential and could be exported to other national and international centers, generating economic returns. While the monetary quantification of the impact of this therapy is challenging, its benefits in terms of quality of life and its potential advantages for transplanted patients underscore its significant relevance to healthcare systems.

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