Injectable Biomaterial Systems for Immuno-Oncology
Koshy, Sandeep Tharian
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AbstractEnhancing the function of the immune system has proven effective in treating human cancers. While effective in some patients, injection of these immunomodulatory drugs and therapeutic immune cells can lead to severe immune-related toxicities at off-target locations, leading to the withdrawal of many patients from these potentially life-saving therapies. Additionally, poor localization and persistence of cells and drugs is seen with soluble formulations, potentially limiting treatment efficacy. There is a pressing need for delivery systems that overcome these challenges.
The objective of this thesis is to design and validate injectable biomaterial systems for drug and cell delivery for immuno-oncology applications. Biomaterial systems have been used to precisely control the spatiotemporal delivery of biological agents. Though biomaterials have recently been used to enhance immunotherapies, a number of opportunities exist for developing new biomaterial-based strategies to enhance anti- cancer immunity. In this thesis, first, a nanoformulation approach is used to improve the intracellular delivery of a recently developed immune adjuvant requiring entry into the cytosol for its action. Second, two new injectable covalently crosslinked hydrogel systems are produced that form without harming encapsulated biological species, alleviating a major problem with the current widely used hydrogel-based cell and drug delivery systems. Third, a strategy for creating injectable shape-memory hydrogels is presented that allows minimally invasive delivery of preformed cell and drug-delivering hydrogels into the body to locally modulate immune cell function. Next, a facile method that allows controlled and tunable release of a number of bioactive immune proteins from hydrogels is shown. Finally, the new material systems developed in this thesis are applied to immuno-oncology applications including cancer vaccination, intratumoral immune- modulation, collection of antigen-specific T cells from the blood, and local delivery of T cells to tumor sites. This thesis extends the biomaterials toolbox available for controlling the delivery of cells and drugs. This work demonstrates that injectable biomaterials can be used to coordinate complex immunological processes, opening up new therapeutic opportunities in cancer immunotherapy.
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