Developing strategies to enhance immune responses induced by mesoporous silica rod vaccines

Abstract

Therapeutic cancer vaccination can stimulate the immune system to specifically eradicate tumor cells and establish long-term memory to prevent tumor recurrence. However, an efficacious cancer vaccine has remained elusive. Recently, we developed a biomaterial scaffold-based cancer vaccine based on mesoporous silica rods (MPS) that is capable of mobilizing large numbers of antigen-presenting cells (APCs) to drive potent tumor-specific T cell responses and significant tumor control. However, there is still an incomplete understanding of the factors driving the potent immune responses elicited by MPS vaccines. Furthermore, current MPS vaccines are not curative in poorly immunogenic murine solid tumor models, which are representative of the “cold” solid tumor phenotype that is resistant to immunotherapy in humans. In this thesis, we addressed these challenges by first quantifying and phenotyping the APC subsets engaged by MPS vaccines at key tissue sites. Although MPS vaccines drove robust expansion of all APC subsets, the most pronounced phenotypic changes were observed in conventional dendritic cells (cDCs), the APC subset specialized in priming antitumor T cells. Considering this result, we developed a therapeutic regimen centered around MPS vaccines that enabled greater engagement of cDCs. Combination of MPS vaccination with CD122-biased IL-2/anti-IL-2 antibody complexes led to synergistic cDC engagement at key tissue sites, enabling more potent tumor-specific CD8+ T cell responses and more robust therapeutic efficacy in tumor models relative to either monotherapy. In the final part of this thesis, we explored a key aspect of the mechanism of action of MPS vaccines that remains poorly understood, namely the effect of modulating adjuvant release kinetics on adaptive immune responses elicited by MPS vaccines. Using a facile surface modification approach to tune adjuvant release kinetics, we demonstrated that rapid release of the TLR9 agonist CpG from MPS vaccines is critical for generation of potent cytotoxic CD8+ T cell responses and robust, Th1-skewed IgG2a/c antibody titers. Together, this thesis sheds light on key principles underlying the potency of MPS vaccines and establishes that factors that enhance engagement of cDCs can boost the potency of therapeutic cancer vaccines.