Thursday, May 22, 2025
5/22/2025
Lymph node inspired hydrogels for immune cell reprogramming - Summary Abstract This proposal combines the fields of DNA origami, colloids, and supramolecular hydrogels to develop biomimetic scaffolds to transform the way we engineer T cells for cellular immunotherapy. Cell therapies have broad biomedical potential, spanning application areas as diverse as cancer, cardiovascular disease and autoimmune disorders – but realizing this potential is proving difficult due to significant challenges involved with producing large numbers of engineered T cells, which is done through an arduous ex vivo process. These challenges have made T cell therapies among the most expensive medical treatments, costing as much as $400,000 per treatment and requiring as much as 100 days to produce antigen-specific T cell therapies. Despite this time and expense, current methods also suffer from a risky ‘one-patient, one-batch’ approach that can lead to failed or low-quality cell products. These difficulties are unsurprising since engineering T cells is inherently complex and requires replicating the sophisticated process by which T cells are programmed in the body. Endogenously, this involves an intricate dance between T cells and antigen presenting cells within highly specialized lymph nodes. The process is tightly regulated through subcellular, cellular and tissue-level features within the lymph node, but the way that T cells are engineered commercially bears minimal resemblance to this process. Efforts to develop more biomimetic technologies to improve T cell engineering have only focused on individual aspects of this process. Moreover, current commercial efforts are focused on incremental improvements to the current status quo of ex vivo T cell engineering, rather than pursuing new strategies to engineer T cells directly in vivo. We propose a new modular platform technology that mimics lymph nodes, recapitulating the sub-cellular, cellular, and tissue level cues that T cells would encounter in the body. Our approach uses the unique advantages of DNA origami to gain nanoscale spatial control over key signaling ligands, and then integrates these constructs into an injectable supramolecular hydrogel that can be used to program and expand T cells directly in living systems. I am ideally positioned to pursue this research given my extensive training in multifunctional nanomedicine and in supramolecular biomaterials, which includes technical expertise in nanofabrication, materials characterization, mammalian tissue culture, gene delivery, flow cytometry, multiplexed immunoassays, molecular imaging and preclinical animal work. The prototype design in this proposal will be capable of both polyclonal and antigen- specific T cell expansion and stands to benefit both ex vivo methods as well as open new horizons for in vivo T cell engineering. We expect that with R21 funding to develop our prototype, we will obtain R01 funding to pursue long-term goals using antigen-specific in vivo T cell engineering to treat specific diseases.
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