Immunoengineering Approaches for Cancer Immunotherapy and Autoimmune Diseases

Abstract

Immunotherapy, which leverages the host immune system to combat diseases, has thrived in addressing numerous intractable conditions, including cancer, autoimmune disorders, infectious diseases, and allergies. Despite its breakthroughs, significant challenges persist in clinical applications and translational research. Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs), has changed the landscape of oncology, offering prominent benefits in patient survival. However, only 30-50% of patients respond to ICIs, with response rates further diminished by the development of resistance or immune-related adverse events (irAEs), often necessitating treatment interruption or discontinuation. In contrast, therapeutic options for multiple sclerosis (MS), a debilitating autoimmune disorder of the central nervous system (CNS), remain limited to symptomatic management or disease-modifying therapies (DMTs). Restoring immune tolerance to self-antigens in CNS tissue represents an unmet need. However, the translation of therapies from preclinical models to humans is hindered by poorly defined disease mechanisms and individuals' highly diverse repertoire of autoantigens. This dissertation investigates immunoengineering strategies to enhance the efficacy of immunotherapy by addressing these challenges. Specifically, it explores: (1) the role of inulin's degree of polymerization (DP) in its gelling properties and synergy with ICIs for cancer treatment, (2) the tolerability and impact of inulin gel on gut microbiome composition in phase I clinical trial, and (3) the application of synthetic high-density lipoprotein (sHDL) nanodiscs for delivering MS-related antigens to induce immune tolerance. In the first study, a dietary fiber-based strategy was developed to potentiate ICIs using engineered inulin gel. Higher DP inulin increased gel viscosity, prolonged colon retention, and enhanced short-chain fatty acid (SCFA) production. In murine tumor models, oral administration of inulin gel synergized with anti-PD-1 therapy in a DP-dependent manner. High DP inulin modulated the gut microbiome by increasing the relative abundance of bacteria (e.g., Akkermansia) reported in the literature to improve ICI responses while reducing pro-inflammatory strains associated with colitis. Elevation in systemic SCFA levels further enhanced anti-tumor immunity and implied protective effects against ICI-induced colitis. The second study evaluated an optimized inulin gel formulation in a phase I clinical trial. The inulin gel, designed for large-scale production with increased viscosity (~10-fold) and improved shelf-stability (> 6 months), was well-tolerated at a daily dose of 20 grams over ten days in healthy subjects. Inulin gel resulted in significantly higher fecal propionate levels than inulin powder, indicating promoted SCFA fermentation. In the third study, nanodisc-based inverse vaccines were developed to deliver MS-associated autoantigens in experimental autoimmune encephalomyelitis (EAE), a widely used murine model for MS. The nanodiscs effectively induced antigen-specific regulatory T cells (Tregs), halted epitope spreading, and exerted therapeutically significant bystander suppression. These findings demonstrated the potent efficacy of nanodisc in addressing key clinical challenges in MS, such as autoantigen heterogeneity and epitope spreading, by fostering immune tolerance. Mechanistic studies suggested the indispensable roles of Tregs and tolerogenic dendritic cells (DCs) in mediating this tolerance. In summary, this thesis demonstrates the potential of immunoengineering approaches to advance therapeutic innovations for both immune activation and suppression. These findings provide a foundation for broader clinical applications, offering promising strategies to improve cancer immunotherapy and to address autoimmune diseases.