Immunoengineering Approaches for the Treatment of Cancer and Prevention of Infectious Diseases

Abstract

The field of immunoengineering is highly interdisciplinary, involving the insights from various other fields of studies such as physiology, computation, pharmacology, materials science and many more. With the recent progress in technology development, analyzing detailed cellular interactions that constitute the immune system has become possible, and many more biological and engineering tools became within reach for precise investigation and modulation of immune responses. As a result, many breakthroughs have been achieved in various clinical settings. Immunotherapies, such as anti-PD-1 antibody and chimeric antigen receptor T cells, revolutionized cancer immunotherapy, while genome sequencing and nanotechnology allowed for the rapid development of various vaccines in response to the recent outbreak of Coronavirus Disease 2019. Also, analysis of massive amount of data collected from the bacterial genome within various parts of the body, called the microbiome, is enabling us to study the relationship between the microbiota and human body and health, and is suggesting new ways of treating once thought to be hard-to-treat diseases. In Chapters II and III, strategies for modulating the immune responses using biomaterials for cancer immunotherapy are introduced. Chapter II describes silica-based nanoparticle-mediated stimulator of interferon gene (STING) agonist delivery. Compared to soluble form of STING agonist, it induced ~4-fold higher dendritic cell activation in vitro, accompanied by significantly enhanced cytokine secretion, which together with prolonged immune cell activation within the tumor microenvironment, greatly improved therapeutic efficacy of the STING agonist in mouse melanoma models. In Chapter III, an adjuvant and a model neoantigen peptide were formulated into a nanoparticle, which increased dendritic cell activation and antigen presentation by 2~4 folds and 4-folds, respectively in vitro compared to soluble formulation. It translated to ~3 folds higher antigen-specific CD8+ T cell frequency in blood circulation in mice. In addition, an attempt to induce a stronger chemokine gradient to recruit more T cells to tumor from the blood circulation was also investigated. In Chapter IV, use of lipid-based nanoparticle to formulate vaccines against infectious diseases, including human immunodeficiency virus-1 (HIV-1) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is introduced. The aim of the study was to load subunit proteins into lipid-based nanoparticles while maintaining the structural intactness and to induce enhanced antibody responses when vaccinated to animals. Nanoparticle vaccine enhanced in vitro dendritic cell activation and antigen presentation, while improving antigen trafficking to lymph node in vivo, leading to significantly enhanced IgG responses in animals. In Chapter V, I investigated the effects of prebiotics on gut microbiota and immune responses during cancer immunotherapy using a cancer vaccine. Recently the communication between the gut microbiota and the immune system started to be revealed, thanks to mass data analysis and genome sequencing becoming more available for general research purposes. Also, studies are reporting the correlation of certain bacterial species and their metabolites with immunotherapeutic outcomes during cancer immunotherapies. Here, I sought to investigate the effects of prebiotics consumption on gut microbiota and if changes in bacterial frequencies can modulate the immune responses following cancer vaccination using mouse tumor models. Lastly in Chapter VI, I present the overall review of the studies in this thesis. Also, future directions to pursue are discussed with ways to provide complementing information to some of the experiments, which currently can only suggest limited insights, and potential clinical translation in mind.