Research Project
10282870
PROJECT SUMMARY Despite their transformative promise, traditional cancer vaccines have had poor clinical responses since vaccine-specific systemic T cells often cannot traffic to immunosuppressed ?cold? tumors. Traditional vaccines generate only a lymph node-derived augmentation or ?prime? of systemic CD8+ T cells that are trained to comprehensively seek and eliminate specific target tumor cells. Traditional strategies, however, have been short-sighted in that they have failed to develop methods to recruit these T cells to the ?cold? tumor microenvironment (TME) that advances by building a formidable local immunosuppressive barrier driven largely by dysfunctional innate immune cells. Our strategy seeks to reprogram dysfunctional tumor-resident innate antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, by driving a local anti- tumor immune response with a proinflammatory cytokine gradient that reshapes the TME from non-inflamed and ?cold? to inflamed and ?hot? to recruit or ?pull? systemic T cells in from a ?prime?. In our recent Cancer Research paper (Atukorale et al. 2019) and additional preliminary data, we report on the development of a ?pull? strategy based on a novel immunostimulatory nanoparticle (immuno-NP) that is significant due to key engineering design features. Immuno-NPs co-encapsulate two synergistic immune agonists on the same particle, cdGMP, an agonist of the STING pathway, and MPLA, an agonist of the TLR4 pathway, to promote a robust production of proinflammatory Type I interferon ß in target APCs. Immuno-NPs can be safely delivered in the systemic blood circulation to achieve widespread and preferential deposition in the tumor perivascular regions that are rich in their target APCs. Immuno-NPs drive a powerful local self-amplifying anti-tumor immune response that harnesses otherwise ?exhausted? immunosuppressed local CD8+ T cells as the key effectors of tumor clearance, which suggests highly effective ?cold-to-hot? TME reprogramming. Our central hypothesis is that precise coupling of a standard lymph node-directed CD8+ T cell vaccine ?prime? with a tumor-directed immuno-NP ?pull? for a novel ?prime-pull? approach can provide the key missing link for effective cancer vaccination. Specific Aim 1 will identify optimal function of an immuno-NP pull in terms of immuno-NP design and co-treatment with anti-PD1. Specific Aim 2 will develop a precise ?prime-pull? coupling schedule. Specific Aim 3 will evaluate safety and toxicity for effective dose/scheduling ?prime-pull? regimens. Dr. Atukorale's career goals are to establish a nanomaterials-based cancer immuno-engineering laboratory as an independent investigator. She will develop immuno-nanomaterials tools that drive, quantify, and interrogate immunity, specifically in the context of lethal cancers. Dr. Atukorale's strong career development plan includes significant new research collaborations, a senior advisory committee, research presentations, faculty-level workshops, and plans for subsequent grant proposals. Her future sponsoring institution will be based in both Schools of Medicine and Engineering, in direct line with her highly interdisciplinary research interests.
