Designing a targeted 'super adjuvant' nanoparticle platform for vaccination

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PROJECT SUMMARY This proposal seeks to develop a targeted tri-agonist “super adjuvant” nanoparticle platform for in situ cancer vaccination. Vaccines consist of 2 components: a tumor-specific antigen that is recognized by CD8+ cytotoxic T cells (CTLs) and an adjuvant that provides the necessary costimulatory cytokine signals to antigen-presenting cells (APCs) to prime and activate a CTL response. In complex diseases like cancer, however, a single- adjuvant vaccine may not be fully effective to mitigate the myriad immunosuppressive effects of a heterogeneous aggressive tumor microenvironment (TME) such as that of triple-negative breast cancer (TNBC). Co-delivery of multiple adjuvants in a rationally designed “super adjuvant” formulation can harness multiple pattern recognition receptor pathways simultaneously to drive a proinflammatory synergistic cytokine response that has both breadth and depth. Further, compared to standard vaccination, where a preselected antigen and adjuvant are delivered to lymph nodes, in situ vaccination, where only the adjuvant is delivered directly to the tumor, has clear advantages. In an in situ approach, the tumor itself provides the antigen in the form of neoantigens shed from dying tumor cells. This approach captures patient heterogeneity on a personalized basis and does not require prior knowledge of tumor antigens. Current in situ approaches, including free agonists, free cytokines, and immunogenic viruses, rely heavily on direct intratumoral injection to minimize off-target toxicity and are cancer type-specific. Intratumoral delivery itself also has serious limitations in both delivery and efficacy. Supported by our recent publications and additional preliminary data, this high- risk proposal seeks to address these shortcomings by designing a “super adjuvant” immunomodulatory nanoparticle (immuno-NP) platform that coencapsulates 3 synergistic Type I interferon-driving innate immune agonists on the same NP using lipid-based materials and microfluidics. Specifically, 60-nm PEGylated immuno-NPs will be designed to be delivered safely in the systemic blood circulation to co-deliver agonists of the STING, TLR4, and TLR9 pathways to tumors. They will also be targeted to multiple specific types of cells in the TME, including APCs, activated endothelial cells, and tumor cells, to orchestrate a concerted multi-cellular response that may be necessary to eliminate heterogeneous aggressive tumors. We hypothesize that targeted tri-agonist “super adjuvant” immuno-NPs will drive a synergistic Type I interferon-mediated APC response that activates CTLs for tumor clearance in multiple mouse models of TNBC. Specific Aim 1 will identify immuno-NP design parameters required for optimal function in terms of promoted cytokine breadth and depth. Specific Aim 2 will establish immuno-NP targeting schemes for effective TME homing and therapeutic efficacy. These studies will effectively address the delivery, efficacy, and safety challenges that severely limit current approaches. As a platform technology, successful development of this “super adjuvant” immuno-NP also has wide-ranging applications in standard lymph node-directed vaccination for both cancer and infectious disease.