Periodic Reporting for period 4 - NextGen IO (Exploiting the hypoxia response in T cells for Next-Generation Immuno-Oncology)
Okres sprawozdawczy: 2023-08-01 do 2024-01-31
Context and problem addressed: The NextGen_IO project addresses critical challenges in the field of immuno-oncology, focusing on the exploitation of the hypoxia pathway in T cells for the development of novel cancer treatments. A significant issue in current cancer therapy is the limited effectiveness of state-of-the-art immunotherapies, such as immune checkpoint inhibitors and autologous adoptive T-cell therapies, which are effective only in a small subset of patients. This limitation stems from several factors intrinsic to the tumor microenvironment, including hypoxia, aberrant vascularization, and altered nutrient availability, which severely impair the immune response and the efficacy of therapies.
Importance for society: Enhancing the effectiveness of immunotherapies is crucial for improving cancer treatment outcomes. Successful intervention in the hypoxia pathway can lead to the development of therapies that not only extend the life of cancer patients but also improve their quality of life by reducing the adverse effects associated with less targeted treatments.
he primary objectives of the NextGen_IO project were:
1. To develop a novel small molecule inhibitor to modulate the hypoxic response in T cells.
2. To discover therapeutic targets in T cells, focusing on hypoxia-driven epigenetic modifications.
3. To develop T cell therapies, particularly for the treatment of solid hypoxic tumors.
Conclusions of the Action: Throughout its duration, the NextGen_IO project has met its initial objectives, making significant advances across various research areas:
1. Development of a small molecule inhibitor: A first-in-class small molecule inhibitor targeting Factor Inhibiting HIF (FIH) has been developed, showing efficacy in enhancing T cell responses against tumors.
2. Therapeutic target discovery: Through functional genomics and phenotypic screenings, novel targets crucial for T cell memory differentiation and hypoxia-induced cell surface targets have been identified. Notably, the proteasome was discovered as a critical regulator of T cell exhaustion in the tumor microenvironment.
3. Innovative CAR-T cell therapy development: Hypoxia-inducible molecular switches for CAR-T therapy were developed.
Additionally, the project adapted to emerging global health challenges by contributing to the development of diagnostic methods for identifying neutralising antibodies against SARS-CoV-2. This demonstrates the project's flexibility and broader impact.
These achievements validate the therapeutic potential of the hypoxia pathway. The results have been disseminated through scientific publications laying a robust foundation for future innovations in drug development and therapeutic strategies.
Importance for society: Enhancing the effectiveness of immunotherapies is crucial for improving cancer treatment outcomes. Successful intervention in the hypoxia pathway can lead to the development of therapies that not only extend the life of cancer patients but also improve their quality of life by reducing the adverse effects associated with less targeted treatments.
he primary objectives of the NextGen_IO project were:
1. To develop a novel small molecule inhibitor to modulate the hypoxic response in T cells.
2. To discover therapeutic targets in T cells, focusing on hypoxia-driven epigenetic modifications.
3. To develop T cell therapies, particularly for the treatment of solid hypoxic tumors.
Conclusions of the Action: Throughout its duration, the NextGen_IO project has met its initial objectives, making significant advances across various research areas:
1. Development of a small molecule inhibitor: A first-in-class small molecule inhibitor targeting Factor Inhibiting HIF (FIH) has been developed, showing efficacy in enhancing T cell responses against tumors.
2. Therapeutic target discovery: Through functional genomics and phenotypic screenings, novel targets crucial for T cell memory differentiation and hypoxia-induced cell surface targets have been identified. Notably, the proteasome was discovered as a critical regulator of T cell exhaustion in the tumor microenvironment.
3. Innovative CAR-T cell therapy development: Hypoxia-inducible molecular switches for CAR-T therapy were developed.
Additionally, the project adapted to emerging global health challenges by contributing to the development of diagnostic methods for identifying neutralising antibodies against SARS-CoV-2. This demonstrates the project's flexibility and broader impact.
These achievements validate the therapeutic potential of the hypoxia pathway. The results have been disseminated through scientific publications laying a robust foundation for future innovations in drug development and therapeutic strategies.
Overview of work performed: Throughout the NextGen_IO project, we have made significant advances in the field of immuno-oncology, specifically focusing on the modulation of the hypoxia pathway in T cells and its applications in cancer therapy. Despite some delays due to lockdowns in 2020, particularly affecting in vivo methodologies, the majority of our work has progressed as planned, culminating in substantial achievements across several key research areas.
1. Development of a novel small molecule inhibitor to modulate the hypoxic response in T cells: We aimed to develop a first-in-class inhibitor of Factor Inhibiting HIF (FIH). This endeavor began with virtual screenings conducted by an external subcontractor, leading to the identification of three series of chemical compounds as hits.The progress in this area has been supported by an ERC Proof of Concept grant submitted in late 2021 to facilitate further drug discovery and technology transfer activities.
2. Therapeutic target discovery in T Cells, focused on hypoxia-driven epigenetic modifications: Using RNA sequencing and proteomic analyses on various cell populations, we identified several molecules with therapeutic potential within the tumor microenvironment, including Syndecan-3 and various epigenetic enzymes. Notably, components of the proteasome were identified as critical regulators of T cell exhaustion. This discovery led to the development of tools to assess T cell exhaustion and strategies to rescue cytotoxicity under hypoxia.
3. Development of T cell therapies for the treatment of solid hypoxic tumors: We focused on optimising CAR-T cell therapies for solid tumors by refining ex vivo expansion methods to enhance CAR-T cell persistence post-infusion.
Moreover, the successful application of two ERC Proof of Concept grants has supported the creation of a spin-off company. This venture aims to commercialise the innovative technologies developed during the project, emphasising the project's role in enhancing technology transfer and economic growth in the biotechnology sector. These efforts underscore the NextGen_IO project's commitment to advancing scientific understanding and developing new therapeutic strategies in immuno-oncology, with an impact on both academic research and clinical applications.
1. Development of a novel small molecule inhibitor to modulate the hypoxic response in T cells: We aimed to develop a first-in-class inhibitor of Factor Inhibiting HIF (FIH). This endeavor began with virtual screenings conducted by an external subcontractor, leading to the identification of three series of chemical compounds as hits.The progress in this area has been supported by an ERC Proof of Concept grant submitted in late 2021 to facilitate further drug discovery and technology transfer activities.
2. Therapeutic target discovery in T Cells, focused on hypoxia-driven epigenetic modifications: Using RNA sequencing and proteomic analyses on various cell populations, we identified several molecules with therapeutic potential within the tumor microenvironment, including Syndecan-3 and various epigenetic enzymes. Notably, components of the proteasome were identified as critical regulators of T cell exhaustion. This discovery led to the development of tools to assess T cell exhaustion and strategies to rescue cytotoxicity under hypoxia.
3. Development of T cell therapies for the treatment of solid hypoxic tumors: We focused on optimising CAR-T cell therapies for solid tumors by refining ex vivo expansion methods to enhance CAR-T cell persistence post-infusion.
Moreover, the successful application of two ERC Proof of Concept grants has supported the creation of a spin-off company. This venture aims to commercialise the innovative technologies developed during the project, emphasising the project's role in enhancing technology transfer and economic growth in the biotechnology sector. These efforts underscore the NextGen_IO project's commitment to advancing scientific understanding and developing new therapeutic strategies in immuno-oncology, with an impact on both academic research and clinical applications.
The NextGen_IO project has made significant advancements beyond the current state of the art in cancer therapy by strategically leveraging the hypoxia pathway in solid tumors to develop innovative therapeutic strategies. Our focus on modulating the hypoxic environment to enhance the efficacy of T cell therapies, particularly CAR-T cells, positions us at the forefront of advanced therapeutic development. During the course of the project, we have developed a first-in-class small molecule inhibitor targeting FIH. The unexpected challenge posed by the COVID-19 pandemic highlighted the project’s adaptability and responsiveness. We expanded our research scope to include the development of methodologies for identifying neutralising antibodies against SARS-CoV-2, enhancing our capabilities in bioinformatics and decentralised operations, and ensuring continuity and innovation without substantial deviations or delays.
Expected and achieved results: By the conclusion of the project, we have achieved several outcomes:
- IP and Technology Transfer: We have successfully filed a patent application, covering the novel therapies and technologies developed. These innovations are the foundation of a new spin-off company.
- Collaborations and industry engagement: The project has reinforced and expanded our interactions with the pharmaceutical industry through collaborations. These partnerships have been crucial for both advancing our research and facilitating the practical application of our discoveries in real settings.
- Training and development: We have committed to training the next generation of researchers, with six PhD projects initiated during the project period.
- Publications and dissemination: We have achieved significant dissemination of our results, with more than 15 articles published in prestigious journals during the project period. Furthermore, we have leveraged both traditional and innovative dissemination methods to share our findings with the broader scientific community and the public.
Concluding overview: The NextGen_IO project has contributed to the advancement of scientific knowledge and cancer treatment and established a platform for future developments in immuno-oncology. Our work in leveraging the hypoxia pathway and genuine technology transfer, demonstrates the dynamic and impactful nature of this project.
Expected and achieved results: By the conclusion of the project, we have achieved several outcomes:
- IP and Technology Transfer: We have successfully filed a patent application, covering the novel therapies and technologies developed. These innovations are the foundation of a new spin-off company.
- Collaborations and industry engagement: The project has reinforced and expanded our interactions with the pharmaceutical industry through collaborations. These partnerships have been crucial for both advancing our research and facilitating the practical application of our discoveries in real settings.
- Training and development: We have committed to training the next generation of researchers, with six PhD projects initiated during the project period.
- Publications and dissemination: We have achieved significant dissemination of our results, with more than 15 articles published in prestigious journals during the project period. Furthermore, we have leveraged both traditional and innovative dissemination methods to share our findings with the broader scientific community and the public.
Concluding overview: The NextGen_IO project has contributed to the advancement of scientific knowledge and cancer treatment and established a platform for future developments in immuno-oncology. Our work in leveraging the hypoxia pathway and genuine technology transfer, demonstrates the dynamic and impactful nature of this project.