A high-throughput nanoparticle assay to characterize cancer neoepitope-specific T cells

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Molecular & Cellular Analysis Technologies
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Not Applicable
ABSTRACTThe application of immunotherapy to cancer has yielded impressive and inspiring results. However, theseresults seem to only apply to a subset of patients. Many practitioners and researchers are aiming to discoverwhy there are differential responses from patients. Yet existing techniques to characterize cancer do not focuson the immune response itself. Therefore, we aim to fill this gap with a technology that directly characterizesthe cancer in terms of its immune response. To do this, we will use a core technology, developed in our labs,that utilizes magnetic nanoparticles to enrich and activate cancer targeting CD8+ T cells to detectable and,potentially even, therapeutic levels. Specifically, we will look for neoepitopes?epitopes generated by themutations of the cancer itself that can generate an immune response. We have demonstrated feasibility of thisapproach within both murine and human contexts; however, we have yet to develop the assay into a high-throughput approach that covers a broad heterogenous human population. To do so, we will first engineer themagnetic nanoparticles, called artificial antigen-presenting cells (aAPCs) because they have both an antigen-loaded human leukocyte antigen (HLA) and co-stimulatory molecules on their surface. Engineering parameterswill include size, ligand density, and ligand choice. Furthermore, we will extend output by developing a 96-wellplate high-throughput version of the assay. We will also broaden the reach of this technology by developingaAPCs for additional class I HLA alleles and also for an aAPC for CD4+ T cell stimulation. Finally, through ourcollaborative efforts with Dr. Jeff Weber at NYU, we will validate the technology by measuring and detectingneoepitopes from stage IV melanoma patients. We will assess how treatment affects the immune response tothe tumor by probing before and after checkpoint blockade therapy. This technology will fill the gap of providingan immunological characterization of cancer in both murine models and critically in patients with cancer. Thisrepresentation will shape both how therapy is delivered and how the next generation of therapies aredeveloped.