Periodic Reporting for period 2 - INsTRuCT (INnovative Training in Myeloid Regulatory Cell Therapy)
Reporting period: 2022-01-01 to 2024-06-30
Chronic immune-mediated diseases are common and greatly impact people’s lives. Current options for treating diseases like rheumatoid arthritis or multiple sclerosis are unsatisfactory because they only control disease progression, but do not cure it. Patients are typically treated lifelong with medicines that suppress their immune system, which improves their symptoms, but makes them more susceptible to infections and some cancers. In future, researchers think it might be possible to re-educate patients’ immune systems to stop harmful reactions by restoring a natural process called “immune regulation” that breaks down in patients.
One high-tech strategy to restore immune regulation in patients is using their own cells as medicine. This approach was studied by researchers in the INsTRuCT Consortium, an MSCA Doctoral Network focusing on scientific and technological innovations in myeloid regulatory cell (MRC)-based therapy. Over 4 years, INsTRuCT’s partners from academia and industry created a framework for advancing original basic scientific discoveries into novel cell products and processes, leading to higher quality immune therapies.
MRC-based therapies represent an attractive strategy for treating chronic immune-mediated diseases. Very importantly, because MRC-based therapy can induce antigen-specific immune non-reactivity, it could be used to treat the root cause of immune-mediated diseases, sparing the toxic effects of general immunosuppression. Moreover, because MRC-based therapy induces a self-reinforcing immune regulation, its clinical effects could be very long-lived. Hence, MRC-based therapy opens the remarkable possibility of curative therapy. First-generation MRC-based cell therapies are now being investigated in early-phase clinical trials across a broad range of indications, including solid organ transplantation, rheumatoid arthritis (RA) and multiple sclerosis (MS). Preliminary success in these proof-of-principle studies justifies their further pharmaceutical development, hopefully leading to their implementation as routine medical treatment over the next 10 to 15 years.
One high-tech strategy to restore immune regulation in patients is using their own cells as medicine. This approach was studied by researchers in the INsTRuCT Consortium, an MSCA Doctoral Network focusing on scientific and technological innovations in myeloid regulatory cell (MRC)-based therapy. Over 4 years, INsTRuCT’s partners from academia and industry created a framework for advancing original basic scientific discoveries into novel cell products and processes, leading to higher quality immune therapies.
MRC-based therapies represent an attractive strategy for treating chronic immune-mediated diseases. Very importantly, because MRC-based therapy can induce antigen-specific immune non-reactivity, it could be used to treat the root cause of immune-mediated diseases, sparing the toxic effects of general immunosuppression. Moreover, because MRC-based therapy induces a self-reinforcing immune regulation, its clinical effects could be very long-lived. Hence, MRC-based therapy opens the remarkable possibility of curative therapy. First-generation MRC-based cell therapies are now being investigated in early-phase clinical trials across a broad range of indications, including solid organ transplantation, rheumatoid arthritis (RA) and multiple sclerosis (MS). Preliminary success in these proof-of-principle studies justifies their further pharmaceutical development, hopefully leading to their implementation as routine medical treatment over the next 10 to 15 years.
INsTRuCT structured its research and training concept around the four major phases of drug development, namely – basic scientific investigation, manufacturing technology, preclinical development, and clinical testing. Through interdisciplinary and intersectoral collaborations, INsTRuCT accelerated MRC-based therapy by carrying forward innovations from one development stage to the next. This research direction will be continued into the future by 15 exceptional early career stage researchers (ESR) who each gained a PhD qualification working with top research groups around Europe.
Specifically, INsTRuCT has made important advances in four areas:
(1) Innovative approaches for generating MRC cell products with greater stability and potency
ESR projects 1-4 and 14 have advanced our understanding of how cellular metabolism influences differentiation of monocytes into MRC. Transcriptomic, epigenetic and functional screening experiments have identified novel molecules and pathways involved in development and stabilization of MRC phenotype and function.
(2) Developing more reliable and affordable manufacturing procedures for MRC-based therapies
ESR projects 5, 7, 8 and 11 have mapped the steps involved in manufacturing of MRC-based therapies, which allows us to better understand the factors contributing to variation in the pharmaceutical quality of MRC products.
(3) Pharmacological characterization of MRC-based cell products
ESR projects 6, 12 and 14 have led to technological developments and new insights into the tissue distribution and immunological functions of MRC after administration.
(4) Studying the impact of patient-related factors on the effectiveness of MRC-based therapies
Through sharing know-how and results within the consortium, ESR projects 9, 10, 13 and 15 made important advances towards establishing assays to stratify patients prior to therapy according to their predicted responses or to measure the immunological effects of MRC-based therapies in patients.
Specifically, INsTRuCT has made important advances in four areas:
(1) Innovative approaches for generating MRC cell products with greater stability and potency
ESR projects 1-4 and 14 have advanced our understanding of how cellular metabolism influences differentiation of monocytes into MRC. Transcriptomic, epigenetic and functional screening experiments have identified novel molecules and pathways involved in development and stabilization of MRC phenotype and function.
(2) Developing more reliable and affordable manufacturing procedures for MRC-based therapies
ESR projects 5, 7, 8 and 11 have mapped the steps involved in manufacturing of MRC-based therapies, which allows us to better understand the factors contributing to variation in the pharmaceutical quality of MRC products.
(3) Pharmacological characterization of MRC-based cell products
ESR projects 6, 12 and 14 have led to technological developments and new insights into the tissue distribution and immunological functions of MRC after administration.
(4) Studying the impact of patient-related factors on the effectiveness of MRC-based therapies
Through sharing know-how and results within the consortium, ESR projects 9, 10, 13 and 15 made important advances towards establishing assays to stratify patients prior to therapy according to their predicted responses or to measure the immunological effects of MRC-based therapies in patients.
From 2020 to 2024, the INsTRuCT Consortium made a substantial scientific, societal and economic impact. Collectively, work from our 15 ESR contributed to 39 scientific publications in major journals, including The Lancet, Cell, Nature Communications, Cellular & Molecular Immunology and Cell Reports. Scientific results from the project are now being exploited through applications in clinical research or commercial development. INsTRuCT continues to communicate about its work with the general public, patient advocacy groups and policy makers. Especially through its online presence and outreach activities, the INsTRuCT Consortium actively promotes the importance of scientific research supported by the EU for the advancement of European society.