Periodic Reporting for period 3 - 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)
Reporting period: 2022-01-01 to 2023-06-30
It is generally accepted that the frequency of immunological diseases is increasing and represents a major public health burden with limited therapy options. Advanced therapeutic medicinal products (ATMP) offer a novel approach to treating highly prevalent diseases. Moreover, instead of simply easing the symptoms, these new therapies, "living drugs", have the potential to restore patients to good health and offer the potential to treat previously incurable diseases. Furthermore, the conventional immunosuppressive drugs administered to manage immunological diseases or acceptance of solid organ transplant are highly toxic and are associated life threatening side effects. Seen as designer medicines, ATMPs have the potential to realizing personalized medicines, with little or no side effects. However, production and handling of these novel products is dependent on developing new highly complex technologies, which pose major challenges to both developers and regulators. ReSHAPE brings together expertise to develop a number of innovative platforms to overcome the challenges, oversee the fruition of novel therapies, making them widely available and affordable.
The number of individuals diagnosed with immunologically related disorders is increasing and current treatment options are limited. ReSHAPE will engineer regulatory T cells (Tregs) to modulate the immune system and help manage the immune disorders and so meet unmet medical needs. The commonly referred to as adoptive transfer of regulatory T cells is a potential game changer in health care. Engineered T regulatory cells will offer a curative option to a large number of patients with immunological diseases. To date these diseases are treated with expansive long-term toxic immunosuppressive drugs with debilitating side effects.
ReSHAPE will strengthen the competitive position of the European Treg therapy and accelerate advanced therapeutics research and development. Advances in this field will enable rapid translation of novel therapies to the clinics, with significant impact on research, economic, public health care services and so reduce the overall public health burden.
The number of individuals diagnosed with immunologically related disorders is increasing and current treatment options are limited. ReSHAPE will engineer regulatory T cells (Tregs) to modulate the immune system and help manage the immune disorders and so meet unmet medical needs. The commonly referred to as adoptive transfer of regulatory T cells is a potential game changer in health care. Engineered T regulatory cells will offer a curative option to a large number of patients with immunological diseases. To date these diseases are treated with expansive long-term toxic immunosuppressive drugs with debilitating side effects.
ReSHAPE will strengthen the competitive position of the European Treg therapy and accelerate advanced therapeutics research and development. Advances in this field will enable rapid translation of novel therapies to the clinics, with significant impact on research, economic, public health care services and so reduce the overall public health burden.
ReSHAPE develops T regulatory cells, a “master cell product”, to attune the immune mechanisms and thereby restore immunological balance. In the 1st phase, ReSHAPE established platforms that accelerated developments in cellular therapy engineering. However, the Covid-19 pandemic severely disrupted ReSHAPE activities. Furthermore, we had to grapple with new regulatory guidelines for cell therapy development. These two unforeseen challenges impeded our progress and the achievement of project milestones. Consequently, we reluctantly had to request an extension of the project timeline, which we anticipate will need to be extended further as well. Despite these difficulties, we have still achieved many significant milestone sand significant progress has been made in various aspects of the project:
1. Next-generation Treg product candidates: We have expanded the range of potential next-generation Treg products that possess redirected specificity, improved stability, and resistance to drugs. These candidates have been thoroughly tested in laboratory settings (WP1), meticulously characterized (WP2), and subjected to in vivo proof-of-concept experiments (WP3). An exciting development includes the advancement of solutions and product candidates for "off-the-shelf" Treg products, aimed at wider accessibility and applicability, based on suggestions from the external advisory board.
2. Advanced gene editing techniques: A major accomplishment is the demonstration of effective and safe virus-free gene editing methods (kock-out/knock-in) in Treg cells (and other cell types) (WP1). These techniques have been successfully transferred to ReSHAPE partners. Additionally, the successful development and delivery of Good Manufacturing Practice (GMP) graded Treg cell lines (1st/2nd generation) (WP4) to partners for product characterization (WP2) and preclinical testing (WP3) have helped navigate regulatory requirements for clinical translation.
3. Enhanced preclinical testing models: Progress has been made in the creation of advanced preclinical models to evaluate new Treg products. This includes adaptations to in vivo murine models and integration of vascularization into microfluidic human-on-chip technology (WP3).
4. GMP process development: Development of GMP processes for 2nd generation Treg (CD8+Treg and TacRes) has progressed, involving the approval of gene editing within the GMP unit (GMO approval). Novel test systems for characterizing these next-generation Treg products have been established, alongside an approved blood collection system to meet new regulatory requirements (WP4).
5. Regulatory approvals and clinical development: Successful scientific advice meetings at institutions like the Paul-Ehrlich Institute have taken place for gene-edited Treg products (TacRes). Furthermore, expansion of manufacturing approval for TacRes has been applied for at local regulatory authorities. Participation in the ATMP pilot program of EMA's Research and Innovation Task Force aims to accelerate clinical development of 2nd generation gene-edited Treg products (WP4).
6. Biomarker portfolio for therapy monitoring: A broad and validated biomarker portfolio for therapy monitoring has been developed. This portfolio encompasses safety, pharmacodynamics/pharmacokinetics, and mode-of-action analyses. These methods have demonstrated feasibility for use in clinical studies (PoC), incorporating advanced analytical techniques like multiparameter flow cytometry, epigenetic analysis, functional assays, and multi-omics approaches (WP5).
7. Health-economic assessment: Cutting-edge early health-technology assessments (early HTA) have been performed to understand the potential value of Treg therapy in solid organ transplantation. This assessment helps in defining targeted success criteria from a health-economic perspective (WP6).
8. Dissemination and Exploitation: The project's website has been regularly updated, and a total of 37 scientific publications have been accepted. Data from ReSHAPE has been shared in various scientific meetings. Additionally, patent applications have been filed to ensure effective development of Treg product candidates up to market approval, enabling commercialization. The project's results have been further exploited for non-project-related endeavors, including the development of gene editing platforms and biomarker-based monitoring systems.
1. Next-generation Treg product candidates: We have expanded the range of potential next-generation Treg products that possess redirected specificity, improved stability, and resistance to drugs. These candidates have been thoroughly tested in laboratory settings (WP1), meticulously characterized (WP2), and subjected to in vivo proof-of-concept experiments (WP3). An exciting development includes the advancement of solutions and product candidates for "off-the-shelf" Treg products, aimed at wider accessibility and applicability, based on suggestions from the external advisory board.
2. Advanced gene editing techniques: A major accomplishment is the demonstration of effective and safe virus-free gene editing methods (kock-out/knock-in) in Treg cells (and other cell types) (WP1). These techniques have been successfully transferred to ReSHAPE partners. Additionally, the successful development and delivery of Good Manufacturing Practice (GMP) graded Treg cell lines (1st/2nd generation) (WP4) to partners for product characterization (WP2) and preclinical testing (WP3) have helped navigate regulatory requirements for clinical translation.
3. Enhanced preclinical testing models: Progress has been made in the creation of advanced preclinical models to evaluate new Treg products. This includes adaptations to in vivo murine models and integration of vascularization into microfluidic human-on-chip technology (WP3).
4. GMP process development: Development of GMP processes for 2nd generation Treg (CD8+Treg and TacRes) has progressed, involving the approval of gene editing within the GMP unit (GMO approval). Novel test systems for characterizing these next-generation Treg products have been established, alongside an approved blood collection system to meet new regulatory requirements (WP4).
5. Regulatory approvals and clinical development: Successful scientific advice meetings at institutions like the Paul-Ehrlich Institute have taken place for gene-edited Treg products (TacRes). Furthermore, expansion of manufacturing approval for TacRes has been applied for at local regulatory authorities. Participation in the ATMP pilot program of EMA's Research and Innovation Task Force aims to accelerate clinical development of 2nd generation gene-edited Treg products (WP4).
6. Biomarker portfolio for therapy monitoring: A broad and validated biomarker portfolio for therapy monitoring has been developed. This portfolio encompasses safety, pharmacodynamics/pharmacokinetics, and mode-of-action analyses. These methods have demonstrated feasibility for use in clinical studies (PoC), incorporating advanced analytical techniques like multiparameter flow cytometry, epigenetic analysis, functional assays, and multi-omics approaches (WP5).
7. Health-economic assessment: Cutting-edge early health-technology assessments (early HTA) have been performed to understand the potential value of Treg therapy in solid organ transplantation. This assessment helps in defining targeted success criteria from a health-economic perspective (WP6).
8. Dissemination and Exploitation: The project's website has been regularly updated, and a total of 37 scientific publications have been accepted. Data from ReSHAPE has been shared in various scientific meetings. Additionally, patent applications have been filed to ensure effective development of Treg product candidates up to market approval, enabling commercialization. The project's results have been further exploited for non-project-related endeavors, including the development of gene editing platforms and biomarker-based monitoring systems.
The overall aim is to reshape undesired inflammation/immunity to help endogenous regeneration as well as engraftment and function of regenerative replacement strategies. Development of 2nd generation regulatory T cell (Treg) will achieve these aims and overcome the limitations of 1st generation Treg products.
Long-term translational results include:
o Novel enabling technology platforms for:
i) Generating next-generation cell products.
ii) Preclinical testing of cell products using human multiorgan-on-chip technique.
iii) Biomarker for cell product characterization and therapy monitoring.
o Novel cellular therapies to reshape undesired immune reactions (therapy class: ATMP).
o Health economic data to develop business (or economic) and reimbursement models.
Long-term translational results include:
o Novel enabling technology platforms for:
i) Generating next-generation cell products.
ii) Preclinical testing of cell products using human multiorgan-on-chip technique.
iii) Biomarker for cell product characterization and therapy monitoring.
o Novel cellular therapies to reshape undesired immune reactions (therapy class: ATMP).
o Health economic data to develop business (or economic) and reimbursement models.