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.
