Veiseh, Omid2023-08-092023-052023-04-21May 2023Nash, Amanda. "Development of Implantable Cytokine Factories for Controlled Modulation of the Immune Response." (2023) Diss., Rice University. <a href="https://hdl.handle.net/1911/115205">https://hdl.handle.net/1911/115205</a>.https://hdl.handle.net/1911/115205EMBARGO NOTE: This item is embargoed until 2029-05-01Cytokines are soluble molecular messengers that activate and propagate disease-fighting immune cascades in the body in response to stimuli from antigen-presenting cells (APC). Many pro-inflammatory cytokines, including IL-2, IL-7, IL-12, IL-15, and IFN-γ, have been tested for anti-tumor efficacy in clinical trials but cannot eradicate tumors without severe off-target effects. However, advances in cell-based therapeutics have enabled effective approaches for genetically engineering cells to produce and secrete proteins continuously. In this work, I have taken advantage of these engineering techniques to genetically engineer cells that continuously produce cytokines and can, thus, be used as living “cytokine factories”. To protect these cells from being rejected in vivo, a porous alginate sphere can be cast around the cells. The ability to fabricate and characterize these cytokine factories, as well as utilize them to initiate and repress immune system responses in vivo, is demonstrated in this work. Briefly, I developed and optimized encapsulated cytokine factories in vitro to tune potency and viability, quantified their ability to activate the immune system with spatial and temporal regulation in multiple pre-clinical mouse models of cancer, evaluated their safety and biocompatibility in rodents and non-human primates, and translated their use into phase I/II clinical trials for women with ovarian cancer. This platform technology can also be rapidly modified to allow for localized immunomodulation in additional diseases including type 1 diabetes, acute respiratory distress syndrome, myocardial tissue repair, and more.application/pdfengCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.drug deliverycell engineeringhydrogelcytokinesimmunotherapycancerThesis2023-08-09