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Dual-targeting nanoparticles for reprogrammed T cell responses in the tumor microenvironment
  1. Alyssa K Kosmides1 and
  2. Jonathan Schneck2
  1. Aff1 grid.21107.350000000121719311Johns Hopkins University Baltimore MD USA
  2. Aff2 grid.21107.350000 0001 2171 9311Johns Hopkins School of Medicine, Department of PathologyInstitute for Cell Engineering Baltimore MD USA

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Meeting abstracts

One of the largest obstacles in cancer immunotherapy involves overcoming the immunosuppressive tumor microenvironment [1]. While many therapies are focused primarily on activating antigen-specific CD8+ T cells, the tumor microenvironment often expresses immunosuppressive cytokines and other immunoregulatory proteins such as checkpoint blockade molecules that diminish their effects [2]. Programmed death ligand 1 (PD-L1) is an inhibitory checkpoint molecule upregulated on many cancers, including melanoma, ovarian cancer, and renal cancer [3]. This can shield a tumor from immune attack by binding to its receptor, PD-1, on T cells. We have developed a nanoparticle platform that combines blockade of PD-L1 with the T cell co-stimulatory signal, anti-4-1BB. This dual targeting system redirects effector cells to recognize target cells while simultaneously blocking checkpoint inhibitors. Antagonistic anti-PD-L1 antibodies and agonistic anti-4-1BB antibodies are conjugated to the surface of biocompatible 50-100 nm iron dextran nanoparticles. The nanoparticles cause a 6-fold increase in IFN-γ production by CD8+ T cells with an exhausted phenotype in the presence of tumor cells in vitro. Additionally, we have shown tumor suppression and a 30% decrease of PD-1 expression in tumor infiltrating lymphocytes in an in vivo B16 mouse melanoma model. This approach may not only reprogram local signaling within the tumor microenvironment, but also promote polyclonal cytotoxic T cell responses in the absence of defining the antigenic specificity of the infiltrating T cells.


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