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The ReSHAPE project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement n. 825392

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ReSHAPE aims at transforming the treatment of patients suffering from undesired Immunity/Inflammation (Allotransplantation, Autoimmunity, Hyperinflammation, and Regenerative Medicine, including Gene Therapy) who presently have limited curative treatment options by applying next-generation Treg approaches that overcome the limitations of 1st generation Treg product developments.

ReSHAPE will use Treg therapy as a very promising new tool for reshaping undesired inflammation/immunity applicable in many disease situations with high unmet medical need which can be used as role model for any approach of next-generation ATMP (Advanced Therapy Medicinal Product).

ReSHAPE will create different platforms, such as a knowledge platform based on previous work of the consortium but also on applying new technology and medical approaches for improved Treg therapies, including next-generation Treg product platform, novel preclinical testing platform, clinical development and clinical trial platform, including accompanying biomarker studies, as well as a HTA/exploitation platform. The platforms comprise the components and expertise necessary to create a solid foundation on which to build new therapeutic Treg approaches and cell products beyond Treg and aim at overcoming particular development bottlenecks.

The ReSHAPE consortium will develop next-generation Treg products and will prove next-generation approaches in clinical trials.

ReSHAPE´s next-generation Treg therapy approaches are applicable for organ and hematopoetic stem cell transplantation and beyond in many medical indication fields, such as Autoimmunity, Hyperinflammation, and Regenerative Therapies, including Gene Therapies.

ReSHAPE´s next-generation Treg approaches will translate a significant technology progress in the advanced therapy field from early development to First-In-Human (FIH) clinical trials with a concept for moving forward further in the added value chain of ATMP implementation.

RESHAPE NEWS

 

2020
23-24Jenuary

Save the date

ReSHAPE First Annual Meeting, January 23-24 2020 (place to be decided)

2019
07February

ReSHAPE Kick Off Meeting, 07-08 February in Berlin (Germany)

30January

ReSHAPE website online

ReSHAPE PROJECT

PROJECT | OBJECTIVES | ORGANIZATION | GLOSSARY

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 in 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.

project

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 own 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

 


TREG CELLS

State of Art

Dynamic tissue homeostasis is based on the crosstalk of intratissue parenchymal, stromal, and immune cells that is guided by the extracellular matrix “code” and regulated in a bi(multi)-directional way. Acute and chronic events such as trauma, ischemia/reperfusion injury, (auto/allo)-immune attack, challenge the homeostasis and result in adaptive processes, including further cellular recruitment. The fate of the tissue response is not only influenced by the strength and duration of the challenges but also by disease modifiers, such as age, malformation, metabolic disbalance.

It is becoming more and more clear that the intratissue balance of inflammation/immunity has a major impact on maintenance/restoration of tissue homeostasis by controlling the state and fate of progenitor/stem/ stromal cells and extracellular matrix dynamics.

Thymically derived FOXP3+ regulatory T cells (tTreg) constitute a unique T cell lineage that is essential for maintaining immune tolerance to self as well as innocuous environmental antigens and intratissue immune homeostasis. However, FOXP3 can also be turned on in conventional T cells with effector functions (Teff) as consequence of antigen exposure in the periphery, under both non-inflammatory and inflammatory conditions. These so-called peripheral Treg (pTreg) that involve both CD4+ and CD8+ pTreg cells, participate in the control of immunity at sites of inflammation. Both tTreg and pTreg can control inflammation/immunity by multiple mechanisms, such as i) competition with Teff for IL-2, ii) through cAMP-mediated immunosuppression, iii) adenosine production via the ectoenzymes, CD39 and CD79, iv) secretion of inhibitory cytokines (e.g. IL-10, TGF-ß, IL-33, IL-34), and v) cytolysis of Teff via granzyme/perforin-dependent mechanisms.

Diminished number and/or function of Treg, e.g. by malformation (e.g. IPEX syndrome), and disbalanced Teff/Treg ratio at the site of inflammation result in unwanted inflammation/immunity associated with autoimmunity, autoinflammation, and disturbed regeneration from trauma and ischemia/reperfusion. Consequently, agonistic targeting of Treg is a promising therapeutic option to combat undesired inflammation/immunity in a broad range of medical indications. Although in vivo Treg induction/expansion approaches, such as blocking co-stimulatory signals during antigen exposure, tolerogenic dendritic cells, tolerogenic peptide vaccination, and low-dose IL-2 show some efficacy in preclinical models and First-In-Human trials, their efficacy is limited and some adverse effects can be observed. In many preclinical models, the adoptive transfer of Treg is more effective. The recent (bio) technological advances to isolate and expand human Treg under GMP compliant conditions, now allow adoptive Treg therapy to be introduced to the clinic, opening up new opportunities.

Treg products (with or without genetic manipulation) for the adoptive transfer are regulatory categorized as Advanced Therapy Medicinal Product (ATMP). ATMP therapies are based on gene, cell or tissue-engineered products which are defined according to the terms of Regulation 1394/2007. So far, only a small number of these products have been placed on the market, not a single Treg product so far.

The ReSHAPE consortium will develop next-generation Treg products and will prove next-generation approaches in clinical trials.

objectives

ReSHAPE PARTNERSHIP

CONSORTIUM | PARTNERS | CONTACTS | RESERVED AREA

The ReSHAPE consortium is coordinated by the Charité Berlin. The project coordinator is MD Petra Reinke is Professor of Nephrology and Transplantation, head of the “Kidney Transplant Outpatient Clinic” at the Dept. Nephrology Charité, and founding director of the Charité Center of Advanced Therapies (BECAT) that 2017 received in a highly competitive procedure 30 Mio € funding by the German Council of Science and Humanities. She is also head of the clinical research field “Immunology and Cell Therapy”, including the GMP core unit, of the Charité-Brandenburg Center for Regenerative Therapies (BCRT), a well-recognized translational center. In addition, she is an honorary member of the Academy of German Urologists and is involved in mentoring programs (e.g. TTS initiative “Woman in Transplantation”; Selma Meyer Mentoring-Program, Heinrich-Heine Universität Düsseldorf; Rahel-Hirsch-Mentoring). Her scientific work focuses on immunological processes that take place during and after transplantation and personalized immunotherapies. She is an expert in GMP manufacturing cell therapeutics, performing investigator-initiated and pharma-sponsored trials (phase I-III) in transplantation, cell therapy, intensive care [..]




HIPGEN EVENTS

Save the date
ReSHAPE First Annual Meeting, January 23-24 2020
Place to be decided




ReSHAPE Kick Off Meeting, 07-08 February 2019
pin Berlin


MEETING DOCUMENTS

pdf   Meeting Agenda

pdf   List of Participants

ReSHAPE DISSEMINATION

PRESS RELEASES

Dissemination material will be available soon.