Cancer Immunology, Immunotherapy

, Volume 64, Issue 3, pp 299–309

Glioblastoma exosomes and IGF-1R/AS-ODN are immunogenic stimuli in a translational research immunotherapy paradigm

  • Larry A. Harshyne
  • Kirsten M. Hooper
  • Edward G. Andrews
  • Brian J. Nasca
  • Lawrence C. Kenyon
  • David W. Andrews
  • D. Craig Hooper
Original Article

DOI: 10.1007/s00262-014-1622-z

Cite this article as:
Harshyne, L.A., Hooper, K.M., Andrews, E.G. et al. Cancer Immunol Immunother (2015) 64: 299. doi:10.1007/s00262-014-1622-z

Abstract

Glioblastomas are primary intracranial tumors for which there is no cure. Patients receiving standard of care, chemotherapy and irradiation, survive approximately 15 months prompting studies of alternative therapies including vaccination. In a pilot study, a vaccine consisting of Lucite diffusion chambers containing irradiated autologous tumor cells pre-treated with an antisense oligodeoxynucleotide (AS-ODN) directed against the insulin-like growth factor type 1 receptor was found to elicit positive clinical responses in 8/12 patients when implanted in the rectus sheath for 24 h. Our preliminary observations supported an immune response, and we have since reopened a second Phase 1 trial to assess this possibility among other exploratory objectives. The current study makes use of a murine glioma model and samples from glioblastoma patients in this second Phase 1 trial to investigate this novel therapeutic intervention more thoroughly. Implantation of the chamber-based vaccine protected mice from tumor challenge, and we posit this occurred through the release of immunostimulatory AS-ODN and antigen-bearing exosomes. Exosomes secreted by glioblastoma cultures are immunogenic, eliciting and binding antibodies present in the sera of immunized mice. Similarly, exosomes released by human glioblastoma cells bear antigens recognized by the sera of 6/12 patients with recurrent glioblastomas. These results suggest that the release of AS-ODN together with selective release of exosomes from glioblastoma cells implanted in chambers may drive the therapeutic effect seen in the pilot vaccine trial.

Keywords

AntisenseExosomeAntibodyDiffusion chamberGL261Glioblastoma

Abbreviations

AS-ODN

Antisense oligodeoxynucleotide

B-FGF

Basic fibroblast growth factor

DiO

3,3′-dioctadecyloxacarbocyanine perchlorate

DLN

Draining lymph nodes

EGF

Epidermal growth factor

FBS

Fetal bovine serum

GBM

Glioblastoma

GM-CSF

Granulocyte macrophage colony stimulating factor

IGF-1R

Insulin-like growth factor type 1 receptor PBS

IL

Interleukin

MFI

Median fluorescence intensity

mDC

Myeloid dendritic cell

PBMC

Peripheral blood mononuclear cells

PBS

Phosphate buffered saline

pDC

Plasmacytoid dendritic cell

Th2

T helper type 2

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Larry A. Harshyne
    • 1
  • Kirsten M. Hooper
    • 1
  • Edward G. Andrews
    • 1
  • Brian J. Nasca
    • 1
  • Lawrence C. Kenyon
    • 2
  • David W. Andrews
    • 1
  • D. Craig Hooper
    • 1
    • 3
  1. 1.Department of Neurological SurgeryThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Department of PathologyThomas Jefferson UniversityPhiladelphiaUSA
  3. 3.Department of Cancer BiologyThomas Jefferson UniversityPhiladelphiaUSA