Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients

• Authors: David H. Chang, Rockefeller University; Keren Osman, Rockefeller University; John Connolly, Rockefeller University; Anjli Kukreja, Rockefeller University; Joseph Krasovsky, Rockefeller University; Maggi Pack, Rockefeller University; Aisha Hutchinson, Rockefeller University; Matthew Geller, Rockefeller University; Nancy Liu, Rockefeller University; Rebecca Annable, Rockefeller University; Jennifer Shay, Baylor Institute for Immunology Research; Kelly Kirchhoff, Rockefeller University; Nobusuke Nishi, Kirin Breweries Co. Ltd.; Yoshitaka Ando, Kirin Breweries Co. Ltd.; Kunihiko Hayashi, Kirin Breweries Co. Ltd.; Hani Hassoun, Memorial Sloan-Kettering Cancer Center; Ralph M. Steinman, Rockefeller University; Madhav Dhodapkar, Emory University
• Journal Title: Journal of Experimental Medicine
• Volume: Volume 201, Number 9
• Publisher: Rockefeller University Press | 2005-05-02, Pages 1503-1517
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1084/jem.20042592
• Subjects: Health Sciences, Oncology; Health Sciences, Immunology
• Keywords: Adult; Blood Chemical Analysis; CD8-Positive T-Lymphocytes; Cell Proliferation; Chemokine CXCL10; Chemokines; Chemokines, CXC; Cytokines; Cytomegalovirus; Dendritic Cells; Flow Cytometry; Galactosylceramides; Humans; Immunotherapy; Interleukin-12; Killer Cells, Natural; Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Vaccination

Abstract

Natural killer T (NKT) cells are distinct glycolipid reactive innate lymphocytes that are implicated in the resistance to pathogens and tumors. Earlier attempts to mobilize NKT cells, specifically, in vivo in humans met with limited success. Here, we evaluated intravenous injection of monocyte-derived mature DCs that were loaded with a synthetic NKT cell ligand, α-galactosyl-ceramide (α-GalCer; KRN-7000) in five patients who had advanced cancer. Injection of α-GalCer-pulsed, but not unpulsed, dendritic cells (DCs) led to >100-fold expansion of several subsets of NKT cells in all patients; these could be detected for up to 6 mo after vaccination. NKT activation was associated with an increase in serum levels of interleukin-12 p40 and IFN-γ inducible protein-10. In addition, there was an increase in memory CD8+ T cells specific for cytomegalovirus in vivo in response to α-GalCer-loaded DCs, but not unpulsed DCs. These data demonstrate the feasibility of sustained expansion of NKT cells in vivo in humans, including patients who have advanced cancer, and suggest that NKT activation might help to boost adaptive T cell immunity in vivo.