Enhancement of Anti-Tumor Immunity Through Local Modulation of CTLA-4 and GITR by Dendritic Cells.

Journal Article

Cancer vaccines have now demonstrated clinical efficacy, but immune modulatory mechanisms that prevent autoimmunity limit their effectiveness. Systemic administration of mAbs targeting immune modulatory receptors CTLA-4 and glucocorticoid-induced TNFR-related protein (GITR) on Treg cells and effector T cells augments anti-tumor immunity both experimentally and clinically, but can induce life-threatening autoimmunity. We hypothesized that local delivery of anti-CTLA-4 and anti-GITR mAbs to the sites where T cells and tumor antigen-loaded DC vaccines interact would enhance the induction of anti-tumor immunity while avoiding autoimmunity. To achieve this goal, DCs transfected with mRNA encoding the H and L chains of anti-mouse CTLA-4 and GITR mAbs were co-administered with tumor antigen mRNA-transfected DCs. We observed enhanced induction of anti-tumor immunity and significantly improved survival in melanoma-bearing mice, without signs of autoimmunity. In human in vitro assays, we demonstrated that DCs transfected with mRNA encoding humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens. Based on these results, this approach of using local delivery of immune modulators to enhance vaccine-induced immunity is currently being evaluated in a Phase I clinical cancer immunotherapy trial.

Full Text

Duke Authors

Cited Authors

  • Pruitt, SK; Boczkowski, D; de Rosa, N; Haley, NR; Morse, MA; Tyler, DS; Dannull, J; Nair, S

Published Date

  • September 9, 2011

Published In

PubMed ID

  • 21905021

Pubmed Central ID

  • PMC3594439

Electronic International Standard Serial Number (EISSN)

  • 1521-4141

Digital Object Identifier (DOI)

  • 10.1002/eji.201041383

Language

  • ENG