Abstract
Cell and gene therapies are revolutionizing the way cancer is treated. CAR-T cell therapies have demonstrated the ability to induce durable remissions or even achieve cures in patients with certain blood cancers that were in final stages, including leukemia and lymphoma. Despite these hopeful results in hematological malignancies, the application of CAR cellular therapies has been more challenging in solid tumors. Solid tumors have a complex tumor microenvironment (TME) that creates barriers to immune cell infiltration and function. This immune-suppressive niche is low in nutrients, highly acidic and hypoxic (lacking oxygen) due to the aberrant metabolism of tumor cells and growth pattern of the tumor. Accumulating data indicates that T cells and NK cells entering this hostile environment are rendered dysfunctional. Up to 90 percent of adult cancers consist of solid tumors, presenting a big need for new therapies. With our research, we aim to enhance the therapeutic potential of NK cell therapies for solid tumor patients in need of new treatment options.
NK cells are cytotoxic cells from the innate immune system that can recognize and eradicate tumor cells swiftly. Their distinct advantages over T cells, including a superior safety profile and potential for allogeneic therapy, make NK cell treatments more economically feasible and logistically appealing, thereby broadening patient accessibility. Until now, efforts to enhance NK cell efficacy in cancer therapy have mainly focused on blocking inhibitory receptors, CAR engineering, or cytokine stimulation. However, recognizing the profound impact of the TME on NK cell metabolism, recent approaches aim to combine immunotherapy with metabolic manipulation to bolster cellular function. This growing awareness underscores the need for innovative engineering and gene editing to develop resilient cellular products capable of thriving in the challenging TME. In this project, we seek to (1) unravel metabolic interventions that boost the metabolic and functional resilience of NK cells in a hypoxic environment; (2) employ CRISPR-Cas9 to stably engineer NK cells based on our discoveries, thereby unlocking their potential in hostile tumor environments; and (3) validate the improved killing capacity and fitness of NK cells in hypoxic conditions using state-of-the-art assays. Driven by the need for novel therapeutic strategies that enhance the overall outcome for cancer patients, we aim to create an innovative NK cellular therapy product that is metabolically rewired to withstand the harsh and suppressive TME.
Researcher(s)
Research team(s)
Project type(s)