(603g) Transforming Immunotherapy with Nature-Inspired Engineering

In adoptive T cell therapy, T cells are extracted from cancer patients, processed ex vivo and then reinfused. A critical step in the processing, T cell activation, is required to promote cell expansion, differentiation and secretion of cytokines, which all contribute to the efficacy of the therapy. The current gold standard approach for ex vivo T cell activation involves stimulating the cells with antibody-coated microbeads. However, this approach is laborious as the beads are non-biodegradable and need to be separated before cell infusion. Furthermore, the design of these materials has overlooked the importance of biophysical parameters which could affect expansion rates and the functionality of cell products. In particular, the T cell receptor (TCR), known for receiving activation signals, is increasingly recognised as a mechanosensor that converts mechanical cues into intracellular biochemical signals. Gaining the ability to harness T cell mechanobiology may therefore provide new ways of fine-tuning the cells for therapy. Taking inspiration from cellular mechano-sensing, we investigated the regulation of T cell activation by substrate stiffness, which has been shown to influence many processes (e.g. differentiation and proliferation) in other cell types. As a proof-of-concept experiment, antibody-coated hydrogels were employed as a stiffness-tunable culture platform to stimulate Jurkat T cells. The stiffness of the hydrogels was varied by controlling the monomer-to-crosslinker ratio. Results showed differential secretion of Interleukin-2 (IL-2) from T cells stimulated on substrates of varying stiffness, suggesting that activation can be mechanically modulated. These findings further our pursuit of designing a material that is both biophysically and biochemically optimised for efficient T cell activation. Moreover, in order to introduce automation and the concept of device modularity to ex vivo cell processing, the hydrogel was integrated with a microfluidic platform. We anticipate that this approach can potentially set the foundations for a new class of T cell processing technology, whereby cell products can be optimised in well-controlled microenvironments for cancer immunotherapy.