Projeto Portugal 2030

Sumário

The ALIVE project tackles a critical challenge in cancer treatment: the limited efficacy of immunotherapies against solid tumors. ALIVE specifically focuses on pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), an aggressive disease with few effective treatments and dismal patient survival rates. Advancing immunotherapies robustness in the focus of pancreatic cancer is a critical, up-to-date challenge, and more effective approaches on this topic are urgently required to make a significant impact where conventional therapies have failed. In this overarching scenario, the core objective of ALIVE is the development of an innovative class of cell-dense living materials for in-situ administration of effector immune system cells exhibiting selective anti-pancreatic cancer activity – Immunoid living materials technology. To realize this, ALIVE aims to combine surface functionalized immune cells and a cell tethering polymer for assembling macro-scale, cell-dense living materials. ALIVE’s enabling technology will be fully based on sugar-driven metabolic glycoengineering of immune precursor cells surface, allowing them to operate as living click-chemistry crosslinkers. ALIVE's immunoid technology builds on the PI's groundbreaking work in metabolic glycoengineering and bioorthogonal click chemistry to manipulate cell surfaces and create interconnected 3D living cell architectures. This method is now to be established here for the first time to unlock the bioengineering of new living materials exhibiting anti-cancer bioactivity, and injectability at unprecedented immune cell densities (ca. >100 million cells), that are clinically relevant for cancer immunotherapy. Envisaging the successful development of ALIVE immunoid living materials technology, the project specifically aims to: 1. Optimize sugar-based metabolic glycoengineering of human immune cells with genetically installed chimeric antigen receptors (CAR- Natural Kiler cells), selectively targeted to pancreatic cancer cells; 2. Functionalize a cell tethering biopolymer with pH-responsive bioorthogonal click-chemistry moieties that enable cell-mediated living materials crosslinking and controlled release in the tumor microenvironment; 3. Fabricate Immune-cell dense living materials and characterize their injectability, cell release profile and bioactivity following confinement in a 3D living architecture; 4. Screen the performance of CAR-NK immunoids in pancreatic cancer 3D preclinical in vitro tumor models and extrapolate the most promising cell formulations to in vivo assays; 5. Evaluate the anti-tumoral efficacy of CAR-NK immunoids in relevant pancreatic cancer in vivo models, this will identify synergistic combinations; ALIVE innovates beyond state-of-the immunotherapies for solid tumors introducing a new concept of: “interconnecting naturally unconnectable living immune cells” – since they naturally exist in suspension as single units. The proposed technological approach allows to transiently interconnect immune human cells, for the first time, leading to hyperdense 3D living materials that can administered locally for potentiating immunotherapy. To materialize the Immunoids technology, ALIVE utilizes an interdisciplinary scientific approach combining metabolic engineering techniques, bioorthogonal chemistry, and immune cells manipulation to create a groundbreaking platform for tackling pancreatic cancer and that can be extended to other solid tumors.