Skip to content

Advertisement

  • Poster presentation
  • Open Access

Dual-targeting nanoparticles for reprogrammed T cell responses in the tumor microenvironment

  • Alyssa K Kosmides1 and
  • Jonathan Schneck2
Journal for ImmunoTherapy of Cancer20142(Suppl 3):P108

https://doi.org/10.1186/2051-1426-2-S3-P108

Published: 6 November 2014

Keywords

MelanomaTumor MicroenvironmentTumor Infiltrate LymphocyteCheckpoint InhibitorIron Dextran

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.

Authors’ Affiliations

(1)
Johns Hopkins University, Baltimore, USA
(2)
Johns Hopkins School of Medicine, Department of Pathology, Institute for Cell Engineering, Baltimore, USA

References

  1. Rabinovich GA, Gabrilovich D, Sotomayor EM: Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007, 25: 267-96. 10.1146/annurev.immunol.25.022106.141609.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Freeman GJ, Sharpe AH, Kuchroo VK: Protect the killer: CTLs need defenses against the tumor. Nat Med. 2002, 8: 787-9. 10.1038/nm0802-787.View ArticlePubMedGoogle Scholar
  3. Kamphorst AO, Ahmed R: Manipulating the PD-1 pathway to improve immunity. Curr Opin Immunol. 2013, 1-8.Google Scholar

Copyright

© Kosmides and Schneck; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Advertisement