Periodic Reporting for period 1 - ITHEMYC (Novel immunotherapies for tuberculosis and other mycobacterial diseases)
Reporting period: 2023-06-01 to 2024-11-30
Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a leading cause of death worldwide. Development of antimicrobial resistance is an important risk during TB treatment, due to the lengthy course of antibiotic therapy and associated adverse events, which can lead to poor medical adherence. Thus, there is an urgent unmet clinical need to develop novel therapeutic modalities that are able to control both drug-sensitive and drug-resistant TB: new drugs that shorten treatment duration and reduce adverse events can improve adherence, and improved treatment outcomes can reduce disease recurrence.
The ITHEMYC project aims to combine current standard of care antibiotics with new immunotherapies as a novel therapeutic strategy. The ITHEMYC project team consists of a multidisciplinary consortium of 11 partners, including two Product Development Partnerships (TBVI, TB-Alliance), eight academic partners with proven immunological expertise and state-of-the-art methodologies and an industrial partner (GSK) involved in vaccine, drug and biomarker R&D for TB. The team will work together to develop immunotherapies by testing (in vitro, in vivo and in silico) several different compounds, such as monoclonal antibodies, therapeutic vaccines, drugs targeting host-pathogen interactions and immunomodulatory compounds for their potential to serve as adjuncts to antibiotic treatments. ITHEMYC aims to efficiently compare promising new treatment regimens and optimize the selection of new TB immunotherapies with the highest clinical potential based on in vitro (Work Package (WP) 1), in vivo (WP2) and in silico (WP3) models available at different partners in the consortium (Fig. 1). In the long term, it is the project’s goal to advance new combined interventions to the clinic in order to improve TB treatment by reducing the duration and toxicity of current antibiotic treatments and relapse rates.
The ITHEMYC project aims to combine current standard of care antibiotics with new immunotherapies as a novel therapeutic strategy. The ITHEMYC project team consists of a multidisciplinary consortium of 11 partners, including two Product Development Partnerships (TBVI, TB-Alliance), eight academic partners with proven immunological expertise and state-of-the-art methodologies and an industrial partner (GSK) involved in vaccine, drug and biomarker R&D for TB. The team will work together to develop immunotherapies by testing (in vitro, in vivo and in silico) several different compounds, such as monoclonal antibodies, therapeutic vaccines, drugs targeting host-pathogen interactions and immunomodulatory compounds for their potential to serve as adjuncts to antibiotic treatments. ITHEMYC aims to efficiently compare promising new treatment regimens and optimize the selection of new TB immunotherapies with the highest clinical potential based on in vitro (Work Package (WP) 1), in vivo (WP2) and in silico (WP3) models available at different partners in the consortium (Fig. 1). In the long term, it is the project’s goal to advance new combined interventions to the clinic in order to improve TB treatment by reducing the duration and toxicity of current antibiotic treatments and relapse rates.
During the first 18 months of the project, in WP1 several cell-based in vitro models (human lung organoids, D. melanogaster TB model & Mtb-Lux-infected THP-1 macrophages) were set up and validated by using test compounds with demonstrated efficacy in in vivo TB models. Next, promising compounds and combinations thereof will be tested in the benchmarked organoid and Drosophila models in the near future. A panel of 11 new compounds was selected following characterization of their ADME (absorption, distribution, metabolism and excretion) properties and safety profile using in silico predictions and in vitro assays, together with an evaluation of their in vitro activity in three different human macrophage models.
In parallel to the activities in WP1, in vivo testing of the most promising immunotherapeutic candidates was initiated in WP2 using four different mouse models provided by project partners at GSK (Kramnik model), IGTP (Kramnik model), JHU (bactericidal Balb/c model) and CNRS (SP140 / C57Bl/6 mouse model) in WP2. Selection by the consortium of the compounds to be evaluated in each of these specialized mouse models took place in two stage gate meetings. Whereas studies testing the compounds selected during the first stage gate meeting will be completed by mid-January 2025, studies assessing the activity of compounds selected in the second stage gate meeting are planned to start early in 2025.
In collaboration with the partners working in WP1 and WP2, set up of an in silico simulation platform based on the UISS-TB framework was initiated within WP3 in period 1 of the project in order to identify optimal treatment options, allowing improved in vitro and in vivo testing of immunotherapeutic compounds.
Based on continued in vitro and in vivo testing and in silico simulation, a limited number of immunotherapeutic therapies will be prioritized for studies in guinea pigs in period 2 of the project.
In parallel to the activities in WP1, in vivo testing of the most promising immunotherapeutic candidates was initiated in WP2 using four different mouse models provided by project partners at GSK (Kramnik model), IGTP (Kramnik model), JHU (bactericidal Balb/c model) and CNRS (SP140 / C57Bl/6 mouse model) in WP2. Selection by the consortium of the compounds to be evaluated in each of these specialized mouse models took place in two stage gate meetings. Whereas studies testing the compounds selected during the first stage gate meeting will be completed by mid-January 2025, studies assessing the activity of compounds selected in the second stage gate meeting are planned to start early in 2025.
In collaboration with the partners working in WP1 and WP2, set up of an in silico simulation platform based on the UISS-TB framework was initiated within WP3 in period 1 of the project in order to identify optimal treatment options, allowing improved in vitro and in vivo testing of immunotherapeutic compounds.
Based on continued in vitro and in vivo testing and in silico simulation, a limited number of immunotherapeutic therapies will be prioritized for studies in guinea pigs in period 2 of the project.
Despite significant progress in the development of novel antibiotics effective against drug-sensitive and drug-resistant tuberculosis strains, advancements in diagnostics and development of new vaccines, shortening the duration of treatment remains a huge challenge, necessitating the development of new treatment options for TB. The ITHEMYC project advances beyond the state of the art by developing innovative adjunctive immunotherapies to shorten treatment duration, improve outcomes and prevent relapse. In addition, this strategy has the potential to be effective against non-tuberculous mycobacteria as well, such as Mycobacterium abscessus and Mycobacterium avium, that cause major problems in patients with chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). This will considerably broaden the use of these types of interventions.