60P Adaptive NK cells as a therapeutic option for childhood leukaemia

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Background: Cell therapy has emerged as a promising approach in cancer treatment, leveraging the potential of the patient's immune system to fight tumors.However, the assessment of the efficacy and safety of these therapies remains a significant challenge, since the current available approaches (i.e.2D cell cultures and animals) have strong limitations in terms of predictability, reliability, and ability to fully mimic the human immune system.This study presents a groundbreaking technological approach in cell therapy testing by integrating 3D patient-derived cancer models with circulating immune cells co-cultured onto an Organ-on-Chip (OoC) platform.Methods: Biologically relevant cancer samples have been optimized by using an alginate-based structure closely resembling the tumor extracellular matrix.Different cancer cell lines (i.e.MDA-MB-231, SKOV-3, HTLA-230) have been embedded in the matrix and cultured up to 2 months under fluid-dynamic conditions with a OOC chamber, simulating the bloodstream.Alternatively, patient derived tumor biopsies have been coated by a thin layer of alginate, to enhance their structural stability over time, and cultured ex vivo in the same OOC.At the same time, peripheral blood mononuclear cells have been injected in the circulatory OOC circuit and their extravasation and tumor infiltration analysed.Results: While tumor cells are able to maintain a good viability, cytoskeleton reorganization and migration within the polymeric matrix up to 2 months of culture, patient derived biopsies displayed a challenging survival ex vivo, although the presence of the fluid flow was able to improve the tumor cells survival.The immune checkpoint ligands PD-L1 and PD-L2 were successfully upregulated by the presence of the IFN-gamma and 3% of PBMC derived natural killer cells were able to leave the circulatory flow, and infiltrate the tumor matrix where they induce apoptosis.Conclusions: A novel fully humanized OOC based platform has been developed to coculture clinically relevant human cancer model, while immune cells are in circulation, with the final aim to deepen insights into the crosstalk among immune /tumor cells and test cellular therapies in a reproducible and reliable way.

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