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ReSHAPE PROJECT

Members of the consortium are pioneers in the development of Treg therapy from basic science to very recent encouraging First-In-Human (FIH) clinical trials of 1st generation Treg products. They have a longtrack record of collaboration, including EC-funded projects (e.g. IOT, RISET, One Study, BIO-DrIM). The first clinical trials were performed to combat organ transplant rejection and Graft-versus-Host Disease (GvHD) post allo-HSC transplantation. However, promising preclinical studies offer a broad application field of Treg therapy beyond allotransplantation. Based on our extensive preclinical and first clinical data, we identified several opportunities for improving Treg therapy which will be addressed by ReSHAPE:


  • Redirecting antigen specificity by CAR/TCR-Treg
  • Enhanced functional stability of Treg under in vivo challenges by innovative genetic and epigenetic modifications of Treg
  • Support of Treg engraftment in vivo by particular conditioning of the recipients and/or enabling Treg to secrete their rown growth factors
  • New in vitro & in vivo tools for in-depth characterisation of Treg product candidates for better standardisation of the manufacturing process and preclinical PoC studies with enhanced predictive value for derisking clinical development 
  • Clinical trials accompanied by a broad portfolio of highly standardised biomarkers to better understand the complex “living” medicinal products regarding their therapy response, such as PK/PD, safety, mode-of-action, putative surrogate markers of efficacy
  • Research to generate innovative clinical development roadmaps and early health economic assessment to support the development of business models for next level of clinical development and commercial exploration of innovations

ReSHAPE OBJECTIVES

Based on our analysis of very recent preclinical and clinical studies on 1st-generation Treg products, we aim at developing next-generation Treg approaches with enhanced efficacy. The main objectives of the ReSHAPE project are:

  • To improve the antigen specificity of Treg products by generating i) Chimeric Antigen Receptor-expressing Treg (CAR-Treg) or ii) specific T cell receptor-expressing Treg (TCR-Treg)
  • To stabilize the in vivo suppressive function of Treg by i) epigenetic FOXP3 gene modification, ii) CRISPR/CAS9 mediated knocking-out of switch-points – receptors whose activation leads to loss of Treg function or even to the switch to effector cells, or iii) mitochondrial modification iv) exploring CD8+ Treg as an alternative and/or complementary to CD4+ Treg, v) inducing resistance to immunosuppressive drugs using CRISPR/CAS9 mediated knocking-out of their target molecules
  • To develop virus-free gene transfer into Treg (vector-free CRISPR/Cas9 technology, transposons...)
  • To develop and validate state-of-the-art technologies for cell characteristics by new in vivo (modified “humanized” rats/mouse models) and in vitro (organ/human-on-the-chip technology) preclinical models, including robust potency tests
  • To improve in vivo engraftment of adoptively transferred Treg by specific local/systemic conditioning of the recipients
  • To explore the feasibility of application for new medical indications beyond transplantation and using allogeneic off-the-shelf Treg products 
  • To apply a broad biomarker portfolio to monitor therapy response and perform mechanistic side studies
  • To perform an early Health Technology Assessment (HTA) for the development of robust business models for the new Treg products

objectives

ORGANIZATION OF THE WORK


The specific objectives of ReSHAPE will be achieved in seven work packages.

WP1: Next-Generation Treg product development platform
WP1 deals with the generation and GMP manufacturing of next-generation Treg products and is the central element of innovation within ReSHAPE. WP1 will focus on innovative concepts, including non-viral approaches, to enhance target antigen specificity and functional stability of Treg even under challenging in vivo conditions. WP1 will also attempt to develop a concept for using allogeneic off-the-shelf Treg products that would enhance their applicability and cost effectiveness. The Next-Generation Treg platform will be used a role model for any next generation ATMP development.

Transfer from Next-Generation Treg platform (WP1) to Next-Generation Test platform (WP2)
Before transferring the new product candidates to the following platforms, a GO/NO Go checkpoint will be applied.

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Criteria:
- Advantages to other Treg products/product candidates
- Robust, reproducible manufacturing feasible
- GMP compatibility feasible
- Sufficient yield feasible
- Cost effectiveness for given indication (early HTA)


WP2: Next-Generation test platform for the characterization of Treg products
WP2 focusses on the in-depth characterization of the different Treg product candidates through Proteomics, Multiparamenter Flow/Mass Cytometry, Molecular signature and the development of robust potency tests. The Next-Generation test platform for characterization of Treg products will be used a role model for the in-depth characterization of any Next-Generation ATMP.

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Spade analysis of Cytof data of human T-cell subsets

Transfer from Next-Generation Test platform (WP2) to Next-Generation Preclinical in vitro and in vivo platform (WP3)

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Criteria:
- Advantages to other Treg products/product candidates
- Stable and reproducible phenotype and function
- Sufficient yield from GMP manufacturing feasible Selection of the appropriate animal model(s) for the respective Treg product candidate is a key issue.


WP3: Next-Generation platform for new in vivo and in vitro preclinical (disease) models
WP3 deals with preclinical models to perform PoC studies with the most promising next-generation Treg product candidates. Cell therapies, and even more gene-manipulated cells are very complex medicinal products because they are “living” drugs that do not follow conventional pharmacokinetic/pharmacodynamic (PK/PD) rules. Therefore, conventional preclinical models are of limited value. Consequently, there is a high unmet need to develop preclinical models that reflect better the clinical challenges and have a higher predictive value. ReSHAPE addresses these challenges by building-up a unique preclinical test platform for Treg products in particular but adaptable for cell & gene therapies in general. The promising Treg product candidates will be tested in selected and appropriate in vivo/in vitro preclinical models. Treg product candidates tested are manufactured GMP compliant to come close to the later clinical grade product.

Transfer from Next-Generation preclinical test platform (WP3) to Clinical Trial platform (WP4) to prove next-generation Treg approaches:

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Criteria:
- Successful PoC in preclinical models
- Stable and reproducible phenotype and function
- Sufficient yield feasible Selection of the appropriate preclinical model(s) of for the respective Treg product candidate is a key issue.


WP4: Clinical Trial platform to prove the Next-Generation Treg approaches
WP4 aims at proving next-generation Treg approaches in four clinical trials:

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Schematic illustration of the Two Study

The two clinical trials Study 2 “ProTreg Study” and Study 3 “Two Study” are almost ready to go (documents/IMPD for regulatory authorities in Germany and UK, respectively, are submitted, or in the final preparation phase) and the Treg product manufacturing authorisation is approved for both GMP units involved, while the planned two FIH clinical trials Study 1 “TacRes” and Study 4 “Eight Treg”(dose escalation up to 3 doses in a classical 3+3 design) in France and Germany are planned to start in  2 years from now.

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Classical design for FIH trials applying dose escalation according to 3+3 scheme

If the development of any additional next-generation Treg product passes the WP1-WP3 pipeline within the 4-year funding period of ReSHAPE (faster as planned), we will make all efforts to prove them in clinical FIH trials as soon as possible too. The FIH trials work as role model for such kind of innovative studies.

It is expected that each of the Treg approaches/products tested in the ReSHAPE cell therapy trials will be classified as “promising” or “not promising” for further investigation in future confirmatory clinical trials and further exploration – accompanying biomarker (WP5) and HTA (WP6) studies support the decision-making.

WP5: Biomarker platform to monitor therapy response to next-generation Treg approaches
WP5 aims to analyze immunological biomarkers accompanying the clinical trials for a better understanding of PK/PD, safety, surrogate markers, mode-of-action.

WP6: Clinical Development research and early Health-Technology Assessment for supporting exploitation strategies and business models for next-generation Treg approaches
This WP focuses on three major areas; clinical study design, regulatory affairs management and health technology assessment (HTA). These activities will be required throughout the entire translation process of the next generation Treg approaches and proactive bridging strategies for future commercialisation. With expertise in pre- and clinical study design, the Berlin team will support WP4 on how to meet required pharmacokinetic and pharmacodynamic objectives and develop a valid clinical study plan with clear primary and secondary endpoints. In addition, the team will be responsible for the regulatory submission procedures via the management and authoring of documents as required for approval by ethics committee and competent authorities (Ehrlich-Institut (PEI)). Moreover, the team will implement HTA methodologies early in the clinical trial phases. Performing pharmacoeconomic studies during clinical development phases has recently been recognized as an essential driver for making favourable reimbursement decisions.

WP7: Dissemination, Exploitation and Communication platform
WP7 deals with dissemination and exploitation of the research results and the communication within the consortium, the international scientific community, patient organisation and public community.

WP8 Management of ReSHAPE
We ensure efficient operational management including that of administrative, financial and legal issues The goal of this WP is to establish and guarantee full synergy, motivation, integration and effective interactions among ReSHAPE participants.

PROJECT GLOSSARY

ATMP Advanced Therapy Medicinal Product
HTA Health Technology Assessment
GvHD Graft-versus-Host Disease
HSC hematopoietic stem cells
FIH First in Human
CAR-Treg Chimeric Antigen Receptor-expressing Treg
TCR-Treg Tcell receptor-expressing Treg
CRISP Clustered Regularly Interspaced Short Palindromic Repeats