Cancer Immunology, Immunotherapy

, Volume 62, Issue 7, pp 1161–1173 | Cite as

Efficient ex vivo induction of T cells with potent anti-tumor activity by protein antigen encapsulated in nanoparticles

  • Rodney A. Rosalia
  • Ana Luisa Silva
  • Marcel Camps
  • Ahmed Allam
  • Wim Jiskoot
  • Sjoerd H. van der Burg
  • Ferry Ossendorp
  • Jaap Oostendorp
Original Article

Abstract

Protein antigen (Ag)-based immunotherapies have the advantage to induce T cells with a potentially broad repertoire of specificities. However, soluble protein Ag is generally poorly cross-presented in MHC class I molecules and not efficient in inducing robust cytotoxic CD8+ T cell responses. In the present study, we have applied poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) which strongly improve protein Ag presentation by dendritic cells (DC) in the absence of additional Toll-like receptor ligands or targeting devices. Protein Ag-loaded DC were used as antigen presenting cells to stimulate T cells in vitro and subsequently analyzed in vivo for their anti-tumor effect via adoptive transfer, a treatment strategy widely studied in clinical trials as a therapy against various malignancies. In a direct comparison with soluble protein Ag, we show that DC presentation of protein encapsulated in plain PLGA-NP results in efficient activation of CD4+ and CD8+ T cells as reflected by high numbers of activated CD69+ and CD25+, interferon (IFN)-γ and interleukin (IL)-2-producing T cells. Adoptive transfer of PLGA-NP-activated CD8+ T cells in tumor-bearing mice displayed good in vivo expansion capacity, potent Ag-specific cytotoxicity and IFN-γ cytokine production, resulting in curing mice with established tumors. We conclude that delivery of protein Ag through encapsulation in plain PLGA-NP is a very efficient and simple procedure to stimulate potent anti-tumor T cells.

Keywords

PLGA OVA Ag cross-presentation Adoptive immunotherapy 

Notes

Acknowledgments

This study was supported by grants from Immune System Activation (ISA) Pharmaceuticals, University of Leiden and the Leiden University Medical Center. We thank Ing. S. Marlina Sibuea for the studies performed to determine the release kinetics of the protein from the PLGA-NP and Ing. W.M.Ramp-Koopmanschap for the analysis of endotoxin levels of the formulated PLGA-OVA batches.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

262_2013_1411_MOESM1_ESM.pdf (53 kb)
Supplementary material 1 (PDF 54 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Rodney A. Rosalia
    • 1
  • Ana Luisa Silva
    • 2
  • Marcel Camps
    • 3
  • Ahmed Allam
    • 2
  • Wim Jiskoot
    • 2
  • Sjoerd H. van der Burg
    • 4
  • Ferry Ossendorp
    • 3
  • Jaap Oostendorp
    • 1
  1. 1.Department of Clinical Pharmacy and ToxicologyLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug ResearchLeiden UniversityLeidenThe Netherlands
  3. 3.Department of Immunohematology and Blood TransfusionLeiden University Medical CenterLeidenThe Netherlands
  4. 4.Department of Clinical OncologyLeiden University Medical CenterLeidenThe Netherlands

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