Periodic Reporting for period 4 - RESHAPE (Reshaping undesired Inflammation in challenged Tissue Homeostasis by Next-Generation regulatory T cell (Treg) Approaches – from Advanced Technology Developments to First-in-Human Trials)
Okres sprawozdawczy: 2023-07-01 do 2024-12-31
Advanced therapies offer a new approach to personalised medicine. Moreover, instead of simply easing the symptoms, these new therapies, called "living drugs", have the potential to restore patients to good health and offer the potential to treat previously incurable diseases. Following the success of such “living drugs” in oncology, numerous preclinical and clinical studies have revealed a new prospect for the sustainable treatment of non-cancer immune disorders using so-called regulatory T cells (Tregs). Tregs are a tiny immune cell subset, called ‘peacemakers’ in our body, and control the strength of an immune response. In contrast to numerous tumor-directed T-cell products, which are already or almost on the market (>20,000 treated patients), no Treg product has yet been approved as a drug. The Treg product candidates need to be further optimised to increase efficiency even further, simplify production and determine the right indications and timing for therapy.
The consortium defined the main tasks to develop and implement innovative next-generation Treg approaches and has brought together the broad expertise of various European partners to make it reality.
Diseases caused by pathogenic immune responses place a great burden on patients and society. More than 10% of adults suffer from autoimmune diseases affecting various organs and some millions of patients live with organ transplants requiring life-long immunosuppression. The major problem is that mostly life-long immunosuppressive treatment is necessary that have in many patients a limited success, many side effects, and induce high direct & indirect costs. The annual global costs of medication and direct healthcare for treating these diseases amount to around €80 bn and €250 bn, respectively. There is therefore a high unmet medical need for novel, more sustainable approaches that rebalance the immune system – to cure rather than treat for life.
In contrast to conventional drugs, Treg can reshape the immune balance, leading to lasting therapeutic effects even after just one treatment. So far, mainly autologous (patient-derived) 1st-generation Treg products have been used, which have achieved very promising results. In order to expand the possible medical indications for Treg therapy, to further increase safety and efficiency and, in the long term, to reduce the costs of therapy by developing off-the-shelf allogeneic Treg products, next-generation Treg therapy approaches should be developed.
ReSHAPE aimed to engineer changes in the clinical landscape for treating patients through the application of novel Treg approaches and thereby by overcome the limitations of 1st-generation Treg products and conventional therapies. This included new therapeutic approaches with 1st generation Treg products, e.g. through patient conditioning, as well as the development of cutting-edge molecular engineering for next-generation Treg candidates with redirected specificity (CAR-Treg), better stability and function, insensitivity to conventional concomitant medications, and off-the-shelf applicability.
Our joint project has advanced knowledge in the field of Treg therapies as well as the development and translational application of new cutting-edge technologies far beyond the original plan. This would hardly have been possible in the same time and quality without the network and financial support from the EU. Due to unforeseen obstacles, such as the Covid-19 epidemic, strategy changes by industry and suppliers, and increasing regulatory requirements, not all milestones were achieved in the clinical studies. However, the continuation of these new Treg studies after the end of the ReSHAPE project is guaranteed by the partners, even though further targeted support from the EU would have been desirable for these projects, which are well advanced in the value chain.
The consortium defined the main tasks to develop and implement innovative next-generation Treg approaches and has brought together the broad expertise of various European partners to make it reality.
Diseases caused by pathogenic immune responses place a great burden on patients and society. More than 10% of adults suffer from autoimmune diseases affecting various organs and some millions of patients live with organ transplants requiring life-long immunosuppression. The major problem is that mostly life-long immunosuppressive treatment is necessary that have in many patients a limited success, many side effects, and induce high direct & indirect costs. The annual global costs of medication and direct healthcare for treating these diseases amount to around €80 bn and €250 bn, respectively. There is therefore a high unmet medical need for novel, more sustainable approaches that rebalance the immune system – to cure rather than treat for life.
In contrast to conventional drugs, Treg can reshape the immune balance, leading to lasting therapeutic effects even after just one treatment. So far, mainly autologous (patient-derived) 1st-generation Treg products have been used, which have achieved very promising results. In order to expand the possible medical indications for Treg therapy, to further increase safety and efficiency and, in the long term, to reduce the costs of therapy by developing off-the-shelf allogeneic Treg products, next-generation Treg therapy approaches should be developed.
ReSHAPE aimed to engineer changes in the clinical landscape for treating patients through the application of novel Treg approaches and thereby by overcome the limitations of 1st-generation Treg products and conventional therapies. This included new therapeutic approaches with 1st generation Treg products, e.g. through patient conditioning, as well as the development of cutting-edge molecular engineering for next-generation Treg candidates with redirected specificity (CAR-Treg), better stability and function, insensitivity to conventional concomitant medications, and off-the-shelf applicability.
Our joint project has advanced knowledge in the field of Treg therapies as well as the development and translational application of new cutting-edge technologies far beyond the original plan. This would hardly have been possible in the same time and quality without the network and financial support from the EU. Due to unforeseen obstacles, such as the Covid-19 epidemic, strategy changes by industry and suppliers, and increasing regulatory requirements, not all milestones were achieved in the clinical studies. However, the continuation of these new Treg studies after the end of the ReSHAPE project is guaranteed by the partners, even though further targeted support from the EU would have been desirable for these projects, which are well advanced in the value chain.
1. Cutting-Edge molecular engineering platform
Focus on synthetic biology that overcome many of the limitations of commonly used viral gene transfer that allows to build-up a LEGO block-like modular, flexible system – several IP could be filed and the platform was proven for next-generation Treg development.
2. Next-generation Treg products
a) Treg with Chimeric Antigen Receptors (CAR-Treg) to target autoimmune diseases, like Type 1 Diabetes = almost ready to go into clinical testing
b) Treg with insensitivity to concomitant standard medications = the first candidate is ready to go into clinical testing in 2025
c) New CD8+ Treg subset = ready to go into clinical testing in 2025
d) Treg expressing higher stability in an inflammatory environment = two candidates identified and ready or almost ready to go in clinical testing
e) “Stealth” Treg allowing off-the-shelf use = entered IMP/IND-enabling phase to achieve maturity for clinical testing
3. In-vitro and in-vivo platforms for in-depth product specification
a) Development of new homologous and “humanized” murine models to test Tregs in vivo
b) Development & validation of novel product release and specification assays at technology platforms
4. Implementation of clinical trials
ReSHAPE designed clinical trials with Treg in UK, France, and Germany – one is finished (data published), the others are ongoing.
5. Dissemination and Exploitation
The consortium published so far >50 papers and filed >15 patents to protect IP. ReSHAPE partners have contributed their expertise to recent European initiatives such as the EU widening program, EU Healthcare Transformation Academy, JOINT4ATMP CSA, and European Rare Disease Research Alliance.
Commercial exploitation: several IP out-licensed to Quell Therapeutics/Astrazeneca and tcBalance Biopharmaceutics; forming of spin-off companies, such as tcBalance and another one in planning; exploitation of technologies by Biotechs (organ-on-chip, biomarker portfolio).
Focus on synthetic biology that overcome many of the limitations of commonly used viral gene transfer that allows to build-up a LEGO block-like modular, flexible system – several IP could be filed and the platform was proven for next-generation Treg development.
2. Next-generation Treg products
a) Treg with Chimeric Antigen Receptors (CAR-Treg) to target autoimmune diseases, like Type 1 Diabetes = almost ready to go into clinical testing
b) Treg with insensitivity to concomitant standard medications = the first candidate is ready to go into clinical testing in 2025
c) New CD8+ Treg subset = ready to go into clinical testing in 2025
d) Treg expressing higher stability in an inflammatory environment = two candidates identified and ready or almost ready to go in clinical testing
e) “Stealth” Treg allowing off-the-shelf use = entered IMP/IND-enabling phase to achieve maturity for clinical testing
3. In-vitro and in-vivo platforms for in-depth product specification
a) Development of new homologous and “humanized” murine models to test Tregs in vivo
b) Development & validation of novel product release and specification assays at technology platforms
4. Implementation of clinical trials
ReSHAPE designed clinical trials with Treg in UK, France, and Germany – one is finished (data published), the others are ongoing.
5. Dissemination and Exploitation
The consortium published so far >50 papers and filed >15 patents to protect IP. ReSHAPE partners have contributed their expertise to recent European initiatives such as the EU widening program, EU Healthcare Transformation Academy, JOINT4ATMP CSA, and European Rare Disease Research Alliance.
Commercial exploitation: several IP out-licensed to Quell Therapeutics/Astrazeneca and tcBalance Biopharmaceutics; forming of spin-off companies, such as tcBalance and another one in planning; exploitation of technologies by Biotechs (organ-on-chip, biomarker portfolio).
The project achieved several breakthroughs, such as i) application of virus-free gene-editing to Treg generation (First-in-Class in clinical trial), ii) novel CAR-Treg for treatment of Typ1-Diabetes, iii) novel Treg CD8+ subset identified and developed to be ready for clinical testing, iv) novel concept and PoC preclinical data for generating off-the-shelf Tregs.
Translational results also include enabling technology platforms for:
i) Generating next-generation cell products
ii) Preclinical testing of cell products
iii) Biomarkesr for cell product characterization and therapy monitoring.
The already high rate of commercial transactions with European companies, both directly (new Treg candidates) and indirectly (technologies), should be emphasised. This will create investments, jobs, competitiveness and long-term benefits for patients in Europe and worldwide.
Translational results also include enabling technology platforms for:
i) Generating next-generation cell products
ii) Preclinical testing of cell products
iii) Biomarkesr for cell product characterization and therapy monitoring.
The already high rate of commercial transactions with European companies, both directly (new Treg candidates) and indirectly (technologies), should be emphasised. This will create investments, jobs, competitiveness and long-term benefits for patients in Europe and worldwide.