PhD Dissertation Defense Announcement: Michael Zhang
Michael Zhang, PhD Candidate
Engineering cellular immunotherapies using lipid-tailed antigen and adjuvant delivery
The immune system is the best long-term defense mechanism against diseases. Immunotherapies are emerging as frontline options to leverage the immune system and treat incurable diseases such as cancer. These treatments include cancer vaccines, adoptive T-cell transfer (ACT), and T-cell adjuvanting drugs. Each immunotherapy strategy has notable drawbacks that can slow or stop continued their development due to lack of therapeutic efficacy or toxicity-related safety concerns. For example, therapeutic cancer vaccines targeting dendritic cells (DCs) elicit marginal anti-cancer responses in patients due to challenges in expanding DCs ex vivo, or barriers in delivering vaccines to DCs in vivo. ACT and T-cell adjuvant therapies have demonstrated tremendous therapeutic potential in treating cancers, but are burdened with toxicity and adverse responses in patients. Engineered biomaterials may address some safety concerns by providing a targeted delivery strategy to immune cells that enhances efficacy per dose while minimizing systemic off-target toxicities. However, many promising biomaterial-based strategies are either highly complex to manufacture, or they are not versatile for use with diverse immune cells, limiting their potential for broad utilization in immunotherapy applications.
In this thesis, we developed a novel delivery system using phospholipid-based biomaterials to expand therapeutic potential of immunomodulatory applications while avoiding strategies that greatly induce toxicities. Lipid biomaterials were chosen to enable rapid delivery of antigens and adjuvants to cell surface and intracellular compartments of diverse immune cells for controlled immune activation. This simple delivery platform can non-genetically engineer immune cells and activate immunological pathways not accessible by systemic drug formulations to enhance anti-cancer T-cell functions. Lipid biomaterials conjugated to major histocompatibility complex (MHC) class I- and MHC II class II-restricted antigens were delivered to diverse antigen presenting cells (APCs), such as DCs, resting B cells, and activated B cells. The antigen-loaded APCs expanded antigen-specific CD8+ and CD4+ T cells, and promoted inflammatory cytokine secretion in vitro. Lipid-conjugated Toll-like receptor (TLR) adjuvants were rapidly inserted into T-cell plasma membranes, directly co-stimulating and expanding T cells in vitro. Rationally delivering lipid-conjugated adjuvants signaled immune pathways initiated from either cell surface or intracellular compartments, controlling desired immune cell activation for cellular immunotherapies. This simple, non-genetic delivery platform of antigens and adjuvants can advance cell-based cancer vaccine designs, or can engineer T cells for ACT and T-cell adjuvant immunotherapies. By using biomaterials and engineering tools, we accessed and modulated immunological pathways in diverse immune cells that were previously difficult or inaccessible, demonstrating immunotherapeutic potential to enhance efficacy while reducing safety concerns from traditional systemic dosing. This drastically broadens the repertoire of combinations immunotherapies, which may increase the long-term therapeutic potential for immunotherapy in human diseases such as cancer.