An injectable, spontaneously assembling biomaterial-based cancer vaccine platform
AbstractCancer immunotherapy has the potential to provide a cure for many patients. Therapeutic cancer vaccination can stimulate the immune system to eradicate tumor cells while sparing normal tissues, and establish long-term memory to prevent tumor recurrence. However, an effective cancer vaccine has remained elusive.
In this thesis, we developed an injectable biomaterial-based cancer vaccine. Mesoporous silica micro-rods (MSR or MPS) were shown to spontaneously assemble to form a 3D scaffold in vivo, and the surface of the MSRs can be chemically modified to modulate immune cell infiltration. When formulated with GM-CSF and CpG, the MSR vaccine modulated host dendritic cell (DC) activation and trafficking. A single injection of the MSR vaccine against a gonadotropin-releasing hormone (GnRH) decapeptide elicited highly potent anti-GnRH response that lasted for over 12 months and was more effective compared to traditional bolus strategies. Moreover, a MSR vaccine directed against a Her2/neu peptide within the Trastuzumab binding domain showed immunoreactivity to native Her2 protein on tumor cell surface. A facile strategy by modifying the MSRs with PEI was demonstrated to further enhance CTL responses against tumor antigens. Impressively, using a HPV-E7 expressing tumor model, we demonstrated that a single injection of the MSR-PEI vaccine completely eradicated large established tumors in over 80% of mice. Finally, when immunized with a pool of recently sequenced B16 melanoma neoantigen peptides, the MSR-PEI vaccine induced therapeutic tumor growth control and synergy with anti-CTLA4 therapy.
The potency, flexibility, and simplicity of the MSR-based vaccine platform may overcome many of the current barriers to unlocking the potential of cancer vaccines. The potency of this approach can effectively drive immune responses against libraries of cancer specific mutations and synergize with other immunotherapies. The flexibility and modularity of this strategy are expected to drastically simplify the construction of cancer vaccines. The simplicity of this approach is highly amenable to clinical translation. Overall, the MSR-based vaccine can serve as an effective and generalizable platform to modulate host immune cell functions for, among others, cancer, infectious diseases and reproductive biology.
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- FAS Theses and Dissertations