Periodic Reporting for period 2 - IP-cure-B (Immune profiling to guide host-directed interventions to cure HBV infections)
Reporting period: 2021-07-01 to 2022-12-31
The overall aim of the IP-cure-B project is to implement a cutting-edge program to develop novel immunotherapeutic treatment concepts to cure chronic hepatitis B virus (HBV) infections.
HBV is a major global public health threat with over 257 million people worldwide chronically infected and over 887,000 deaths per year1. 4.7 million people live with HBV in the European Union (EU) and European Economic Area (EEA)2. W.H.O. estimates that HBV causes almost 40% of the cases of hepatocellular carcinoma (HCC), which is the 2nd leading cause of cancer-related mortality worldwide. HBV kills nearly 900,0000 people around the world each year.
The current prophylactic vaccine has no impact on established chronic infection. The currently available treatments do not eliminate infection; they include nucleoside analogues (NUC) which only suppress viral replication and Interferon alpha (IFN) which induces a sustained off-treatment viral suppression in only a minority of patients.
The specific objectives of the IP-cure-B program are to:
i) perform a proof-of-concept (PoC) clinical trial to evaluate novel immunomodulatory strategies to boost innate immunity and reshape the immune environment in the infected liver to enhance adaptive immunity in order to better respond to stimulation with a therapeutic vaccine;
ii) characterize immune and viral biomarkers and signatures in relevant clinical cohorts that will then be applied to stratify patients for treatment and monitor responses to host targeted therapies;
iii) design, produce and down-select the best therapeutic HBV vaccines and their combinations that will be evaluated in double humanized mouse model together with the same innate immunity boost before entering clinical trial evaluation;
iv) integrate biological and clinical data from mouse models and clinical studies with statistical approaches to model the best combination treatment for chronic hepatitis B (CHB) for future clinical trials;
v) model the effectiveness of the novel cure therapy to tackle the whole spectrum of the disease and different patient populations, and promote an effective uptake by European and other international health systems.
HBV is a major global public health threat with over 257 million people worldwide chronically infected and over 887,000 deaths per year1. 4.7 million people live with HBV in the European Union (EU) and European Economic Area (EEA)2. W.H.O. estimates that HBV causes almost 40% of the cases of hepatocellular carcinoma (HCC), which is the 2nd leading cause of cancer-related mortality worldwide. HBV kills nearly 900,0000 people around the world each year.
The current prophylactic vaccine has no impact on established chronic infection. The currently available treatments do not eliminate infection; they include nucleoside analogues (NUC) which only suppress viral replication and Interferon alpha (IFN) which induces a sustained off-treatment viral suppression in only a minority of patients.
The specific objectives of the IP-cure-B program are to:
i) perform a proof-of-concept (PoC) clinical trial to evaluate novel immunomodulatory strategies to boost innate immunity and reshape the immune environment in the infected liver to enhance adaptive immunity in order to better respond to stimulation with a therapeutic vaccine;
ii) characterize immune and viral biomarkers and signatures in relevant clinical cohorts that will then be applied to stratify patients for treatment and monitor responses to host targeted therapies;
iii) design, produce and down-select the best therapeutic HBV vaccines and their combinations that will be evaluated in double humanized mouse model together with the same innate immunity boost before entering clinical trial evaluation;
iv) integrate biological and clinical data from mouse models and clinical studies with statistical approaches to model the best combination treatment for chronic hepatitis B (CHB) for future clinical trials;
v) model the effectiveness of the novel cure therapy to tackle the whole spectrum of the disease and different patient populations, and promote an effective uptake by European and other international health systems.
The Project Management Team has provided continuous support to the project despite the impact of the COVID-19 crisis and faced the necessity of providing another amendment process to the project. Partners’ compliance to the Consortium Agreement and H2020 financial and GA rules has been continuously monitored and carefully supervised.
Regarding the PoC clinical trial (WP2), the activities focused on the implementation of the clinical trial. Regulatory approvals were obtained for the implementation of the clinical trial. The site initiation meetings were done for the 8 participating centres from December 2021 to June 2022 leading to the participating centres activation. The sponsor has authorised the start of inclusions for 7 of the 8 participating centres. The first participant was randomised in France on March 1st, 2022 and inclusions have started in the 7 active centres (30 patients were screened and 12 patients were enrolled at the end of the reporting period. An independent data safety monitoring board has been implemented and met twice during RP2.
In WP3, the preclinical HBV immune therapy platform supports the design and the study of innovative HBV therapeutic vaccines, evaluates the effects of an immunotherapeutic TLR8 agonist GS-9688 in humanized mice, and performs mechanistic studies in HBV infected hepatocyte cultures. During this second period, the DC- and DREP-based HBV vaccines have been selected, produced, and controlled for their quality. Immunizations of hCD40 transgenic mice have been initiated to demonstrate their immunogenicity in vivo. In vitro cell assays have been set up to show the capacity of the vaccine candidates to stimulate HBV-specific memory T cells of patients. The effects of GS-9688 in target organs are being further characterized in humanized mouse models (choice of the model, dosage, frequency). Lastly, the interplay between liver resident Kupffer cells (KCs) and hepatocytes in response to GS-9688, as well as its effect against HBV, have been characterized by RNA-seq, cytokine profiling and the quantification of viral parameters.
A focus has been made on further validation of the IP-cure-B standard operating procedures for liver fine needle aspirates (WP4). Extensive tests on the HBcrAg and circulating HBV RNAs biomarkers in real life cohorts of untreated and NUC-treated chronically HBV infected patients and in CHB patients co-infected with HDV and HIV have also been developed.
Further development, validation and harmonization of experimental set ups to monitor changes of innate and adaptive immune responses in patients with chronic hepatitis B undergoing new anti-HBV therapies (WP5). Careful set up of conventional as well as novel explorative signalling, metabolic and transcriptional parameters in blood and liver has successfully been completed. Protocols/SOPs and reagents were transferred to 3 clinical sites and validation studies were performed to ensure high-quality cutting-edge immuno-monitoring.
The data science platform (WP6) will be launched at a later stage when the clinical data will be made available by the partners and transferred for analysis to the datawarehouse. These data should allow gathering information from double humanized mice for liver and immune system. These are expected to consolidate the basic elements (cellular half-life, cytokines data…) specific to the HBV infection pathway to adapt the mechanistic within host model already developed by our team.
In WP7, conceptual improvement was made on the structure of the model and led to a simplified representation of the progression of chronic hepatitis B. The structure of the CHB model for the representative population of the clinical trial is almost finalized (WP7). The estimation of parameters to feed the model has also started.
The communication team (WP8) has worked to expand visibility to the IP-cure-B project and raise awareness on the disease and the progress in the search for new cure therapies. IP-cure-B visibility is ensured by a dedicated website and Twitter account. In November 2022, the first laymen event took place with patient communities throughout Europe.
Regarding the PoC clinical trial (WP2), the activities focused on the implementation of the clinical trial. Regulatory approvals were obtained for the implementation of the clinical trial. The site initiation meetings were done for the 8 participating centres from December 2021 to June 2022 leading to the participating centres activation. The sponsor has authorised the start of inclusions for 7 of the 8 participating centres. The first participant was randomised in France on March 1st, 2022 and inclusions have started in the 7 active centres (30 patients were screened and 12 patients were enrolled at the end of the reporting period. An independent data safety monitoring board has been implemented and met twice during RP2.
In WP3, the preclinical HBV immune therapy platform supports the design and the study of innovative HBV therapeutic vaccines, evaluates the effects of an immunotherapeutic TLR8 agonist GS-9688 in humanized mice, and performs mechanistic studies in HBV infected hepatocyte cultures. During this second period, the DC- and DREP-based HBV vaccines have been selected, produced, and controlled for their quality. Immunizations of hCD40 transgenic mice have been initiated to demonstrate their immunogenicity in vivo. In vitro cell assays have been set up to show the capacity of the vaccine candidates to stimulate HBV-specific memory T cells of patients. The effects of GS-9688 in target organs are being further characterized in humanized mouse models (choice of the model, dosage, frequency). Lastly, the interplay between liver resident Kupffer cells (KCs) and hepatocytes in response to GS-9688, as well as its effect against HBV, have been characterized by RNA-seq, cytokine profiling and the quantification of viral parameters.
A focus has been made on further validation of the IP-cure-B standard operating procedures for liver fine needle aspirates (WP4). Extensive tests on the HBcrAg and circulating HBV RNAs biomarkers in real life cohorts of untreated and NUC-treated chronically HBV infected patients and in CHB patients co-infected with HDV and HIV have also been developed.
Further development, validation and harmonization of experimental set ups to monitor changes of innate and adaptive immune responses in patients with chronic hepatitis B undergoing new anti-HBV therapies (WP5). Careful set up of conventional as well as novel explorative signalling, metabolic and transcriptional parameters in blood and liver has successfully been completed. Protocols/SOPs and reagents were transferred to 3 clinical sites and validation studies were performed to ensure high-quality cutting-edge immuno-monitoring.
The data science platform (WP6) will be launched at a later stage when the clinical data will be made available by the partners and transferred for analysis to the datawarehouse. These data should allow gathering information from double humanized mice for liver and immune system. These are expected to consolidate the basic elements (cellular half-life, cytokines data…) specific to the HBV infection pathway to adapt the mechanistic within host model already developed by our team.
In WP7, conceptual improvement was made on the structure of the model and led to a simplified representation of the progression of chronic hepatitis B. The structure of the CHB model for the representative population of the clinical trial is almost finalized (WP7). The estimation of parameters to feed the model has also started.
The communication team (WP8) has worked to expand visibility to the IP-cure-B project and raise awareness on the disease and the progress in the search for new cure therapies. IP-cure-B visibility is ensured by a dedicated website and Twitter account. In November 2022, the first laymen event took place with patient communities throughout Europe.
The major expected results of the IP-cure-B project are as follows:
- Impact for patients: designing and developing novel treatment strategies towards the cure of infection with shorter duration of treatment. It is expected to result in improved quality of life and decreased social stigma.
- Impact for clinicians proposing a treatment paradigm shift with the development of novel combination therapies for CHB with improved cure rates and a better appraisal of novel biomarkers to improve patient selection for treatment and monitoring treatment response.
- Societal impact: t expected to result in long-term reduction in cost and global burden of CHB
- Impact for research: support the design and establishment of innovative research tools in virology and immunology of HBV infection, double humanized mouse model, and novel treatment concepts.
- Economic impact: the unique integrated approach proposed in the IP-cure-B project based on multidisciplinary expertise including virology, immunology, clinical science, and drug development will likely have an economic impact.
- Impact for patients: designing and developing novel treatment strategies towards the cure of infection with shorter duration of treatment. It is expected to result in improved quality of life and decreased social stigma.
- Impact for clinicians proposing a treatment paradigm shift with the development of novel combination therapies for CHB with improved cure rates and a better appraisal of novel biomarkers to improve patient selection for treatment and monitoring treatment response.
- Societal impact: t expected to result in long-term reduction in cost and global burden of CHB
- Impact for research: support the design and establishment of innovative research tools in virology and immunology of HBV infection, double humanized mouse model, and novel treatment concepts.
- Economic impact: the unique integrated approach proposed in the IP-cure-B project based on multidisciplinary expertise including virology, immunology, clinical science, and drug development will likely have an economic impact.