Periodic Reporting for period 1 - iMAClung (Moving cell-based immunotherapies to fight bacterial lung infections into the clinics)
Reporting period: 2024-04-01 to 2025-09-30
Harnessing the immune system to combat global diseases has introduced a new era in modern medicine. The iMAClung
proposal will extend this concept and will pave the way for the first immune cell-based therapy to combat bacterial airway
infections, driving this innovative therapy towards the clinics and exploitation.
As a consequence, the overall action of iMAClung will concentrate on a macrophage-based immunotherapy to fight
bacterial lung infections and to bridge this concept from small animal studies now to humans. Given the seminal concept
and the technology readiness level already achieved (TRL 3/4) for applying macrophage from induced pluripotent stem
cells (iPSC, referred to as iMonoMac) directly into the lung of rodent animals, it is now time to translate this innovation to
relevant pre-clinical systems. Using state-of-the-art pre-clinical models, medical devices as well as knowledge
of experts in the field, iMAClung will overcome hurdles in the process of clinical translation and to reach the bed of patients.
proposal will extend this concept and will pave the way for the first immune cell-based therapy to combat bacterial airway
infections, driving this innovative therapy towards the clinics and exploitation.
As a consequence, the overall action of iMAClung will concentrate on a macrophage-based immunotherapy to fight
bacterial lung infections and to bridge this concept from small animal studies now to humans. Given the seminal concept
and the technology readiness level already achieved (TRL 3/4) for applying macrophage from induced pluripotent stem
cells (iPSC, referred to as iMonoMac) directly into the lung of rodent animals, it is now time to translate this innovation to
relevant pre-clinical systems. Using state-of-the-art pre-clinical models, medical devices as well as knowledge
of experts in the field, iMAClung will overcome hurdles in the process of clinical translation and to reach the bed of patients.
Building on the ERC-StG iPSC2Therapy, which had already demonstrated scalable production and in-vivo antibacterial activity of iPSC-derived macrophages (iMonoMac), iMAClung focused on validating delivery, function and disease targeting in a setting that closely reflects clinical application.
A first core activity was the definition of a clinically meaningful therapeutic scenario for macrophage-based lung therapy. In close interaction with clinicians and lung-disease experts, the project systematically analysed the pathophysiology of acute and chronic airway infections. This led to the identification of chronic bacterial airway diseases, in particular non-cystic-fibrosis bronchiectasis, as a highly suitable target indication. These diseases are characterized by persistent bacterial colonisation, dysfunctional or depleted alveolar macrophages and limited efficacy of conventional antimicrobial therapies. This scientific disease selection provided a biologically well-justified framework for subsequent technical and translational work.
In parallel, iMAClung established and validated a clinically relevant route of administration for therapeutic macrophages. Instead of systemic delivery, the project focused on bronchoscopy-mediated intrapulmonary administration to deposit iMonoMac directly at the site of infection. Clinically approved fibre-optic bronchoscopes were adapted and tested for the delivery of macrophages through their working channels. These experiments demonstrated that large numbers of iPSC-derived macrophages can be transferred through bronchoscopic devices in a controlled and reproducible manner.
A critical technical question was whether the mechanical and fluidic stress associated with bronchoscopy-based delivery affects the viability or biological function of the cells. iMAClung therefore performed a series of follow-up experiments analysing cell recovery, survival and immune phenotype after passage through bronchoscopic devices. These studies showed that iMonoMac maintain high viability and preserve their key macrophage functions, including inflammatory responsiveness and immune activation profiles, after delivery. This provided essential proof that bronchoscopic administration is compatible with a functional macrophage cell therapy.
To further increase the translational relevance of the work, iMAClung tested macrophage delivery and behaviour in pre-clinical lung models that closely mimic human physiology. Using ex-vivo lung perfusion (EVLP) systems with human and porcine lungs, bronchoscopy-guided administration of iMonoMac was performed under clinically realistic ventilation and perfusion conditions. These experiments allowed direct observation of cell deposition, distribution and immediate tissue interaction in living lung tissue, generating valuable safety- and feasibility-relevant data for future clinical development.
Together, these activities enabled the project to integrate cell manufacturing, delivery technology and disease biology into a coherent therapeutic concept. At the end of the project, iMAClung had achieved (i) the definition of a scientifically sound target disease for first-in-human application, (ii) the establishment of bronchoscopy-based intrapulmonary delivery of iPSC-derived macrophages, and (iii) experimental demonstration that this delivery route preserves macrophage viability and function in clinically relevant lung models. These outcomes move iMAClung from a laboratory-based proof-of-principle towards a technically validated and clinically plausible macrophage-based cell therapy for chronic lung infections.
A first core activity was the definition of a clinically meaningful therapeutic scenario for macrophage-based lung therapy. In close interaction with clinicians and lung-disease experts, the project systematically analysed the pathophysiology of acute and chronic airway infections. This led to the identification of chronic bacterial airway diseases, in particular non-cystic-fibrosis bronchiectasis, as a highly suitable target indication. These diseases are characterized by persistent bacterial colonisation, dysfunctional or depleted alveolar macrophages and limited efficacy of conventional antimicrobial therapies. This scientific disease selection provided a biologically well-justified framework for subsequent technical and translational work.
In parallel, iMAClung established and validated a clinically relevant route of administration for therapeutic macrophages. Instead of systemic delivery, the project focused on bronchoscopy-mediated intrapulmonary administration to deposit iMonoMac directly at the site of infection. Clinically approved fibre-optic bronchoscopes were adapted and tested for the delivery of macrophages through their working channels. These experiments demonstrated that large numbers of iPSC-derived macrophages can be transferred through bronchoscopic devices in a controlled and reproducible manner.
A critical technical question was whether the mechanical and fluidic stress associated with bronchoscopy-based delivery affects the viability or biological function of the cells. iMAClung therefore performed a series of follow-up experiments analysing cell recovery, survival and immune phenotype after passage through bronchoscopic devices. These studies showed that iMonoMac maintain high viability and preserve their key macrophage functions, including inflammatory responsiveness and immune activation profiles, after delivery. This provided essential proof that bronchoscopic administration is compatible with a functional macrophage cell therapy.
To further increase the translational relevance of the work, iMAClung tested macrophage delivery and behaviour in pre-clinical lung models that closely mimic human physiology. Using ex-vivo lung perfusion (EVLP) systems with human and porcine lungs, bronchoscopy-guided administration of iMonoMac was performed under clinically realistic ventilation and perfusion conditions. These experiments allowed direct observation of cell deposition, distribution and immediate tissue interaction in living lung tissue, generating valuable safety- and feasibility-relevant data for future clinical development.
Together, these activities enabled the project to integrate cell manufacturing, delivery technology and disease biology into a coherent therapeutic concept. At the end of the project, iMAClung had achieved (i) the definition of a scientifically sound target disease for first-in-human application, (ii) the establishment of bronchoscopy-based intrapulmonary delivery of iPSC-derived macrophages, and (iii) experimental demonstration that this delivery route preserves macrophage viability and function in clinically relevant lung models. These outcomes move iMAClung from a laboratory-based proof-of-principle towards a technically validated and clinically plausible macrophage-based cell therapy for chronic lung infections.
The main scientific result is the demonstration that iPSC-derived macrophages can be delivered directly into the lung by bronchoscopy without loss of viability or function and can be deployed under clinically relevant conditions in ex-vivo perfused porcine lungs. This establishes, for the first time, a technically feasible and scalable method to locally replace or supplement dysfunctional alveolar macrophages in diseased human lungs (in the future). Combined with the definition of chronic airway infections (in particular non-cystic-fibrosis bronchiectasis) as a suitable first-in-human indication, iMAClung now provides a clear translational pathway for a macrophage-based therapy addressing a major unmet medical need.
The potential impact of these results is substantial. From a medical perspective, iMAClung opens a new class of host-directed therapies for chronic lung infections, which could reduce dependence on antibiotics, counteract antimicrobial resistance and improve long-term lung function and patient quality of life. From a technological perspective, the project establishes a platform for local, tissue-targeted delivery of iPSC-derived immune cells, which can be extended beyond infections to inflammatory, fibrotic and oncological lung diseases. More broadly, the successful integration of iPSC-derived macrophages with existing clinical delivery devices positions this approach as a blueprint for future cell-based therapies in solid organs.
To ensure further uptake and success, several key needs must be addressed. First, additional preclinical research is required to generate comprehensive safety, biodistribution and efficacy data in relevant large-animal and human lung models, in order to support regulatory submissions for first-in-human clinical trials. Second, the cell manufacturing process must be further advanced to GMP-compliant production, including standardisation, batch release criteria and long-term stability testing of the iPSC-derived macrophage product. Third, the bronchoscopy-based delivery procedure should be further optimised and standardised as a medical-device–cell-product combination, including regulatory qualification for its intended therapeutic use.
In parallel, regulatory engagement will remain essential, in particular for defining the requirements for Investigational Medicinal Product Dossiers (IMPDs), clinical trial authorisation and combination-product regulation. Finally, continued protection and expansion of intellectual property, together with access to translational funding and industrial partnerships, will be critical to support clinical development, manufacturing scale-up and eventual market entry.
The potential impact of these results is substantial. From a medical perspective, iMAClung opens a new class of host-directed therapies for chronic lung infections, which could reduce dependence on antibiotics, counteract antimicrobial resistance and improve long-term lung function and patient quality of life. From a technological perspective, the project establishes a platform for local, tissue-targeted delivery of iPSC-derived immune cells, which can be extended beyond infections to inflammatory, fibrotic and oncological lung diseases. More broadly, the successful integration of iPSC-derived macrophages with existing clinical delivery devices positions this approach as a blueprint for future cell-based therapies in solid organs.
To ensure further uptake and success, several key needs must be addressed. First, additional preclinical research is required to generate comprehensive safety, biodistribution and efficacy data in relevant large-animal and human lung models, in order to support regulatory submissions for first-in-human clinical trials. Second, the cell manufacturing process must be further advanced to GMP-compliant production, including standardisation, batch release criteria and long-term stability testing of the iPSC-derived macrophage product. Third, the bronchoscopy-based delivery procedure should be further optimised and standardised as a medical-device–cell-product combination, including regulatory qualification for its intended therapeutic use.
In parallel, regulatory engagement will remain essential, in particular for defining the requirements for Investigational Medicinal Product Dossiers (IMPDs), clinical trial authorisation and combination-product regulation. Finally, continued protection and expansion of intellectual property, together with access to translational funding and industrial partnerships, will be critical to support clinical development, manufacturing scale-up and eventual market entry.