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

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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.

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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

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Acknowledgments

Financial Support: The Albert Stevens Foundation (David W. Andrews).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neurological Surgery, Thomas Jefferson University, 1020 Locust St, rm 454, Philadelphia, PA, 19107, USA

    Larry A. Harshyne, Kirsten M. Hooper, Edward G. Andrews, Brian J. Nasca, David W. Andrews & D. Craig Hooper

  2. Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA

    Lawrence C. Kenyon

  3. Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA

    D. Craig Hooper

Authors
  1. Larry A. Harshyne
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  2. Kirsten M. Hooper
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  3. Edward G. Andrews
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  6. David W. Andrews
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Correspondence to Larry A. Harshyne.

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Harshyne, L.A., Hooper, K.M., Andrews, E.G. et al. Glioblastoma exosomes and IGF-1R/AS-ODN are immunogenic stimuli in a translational research immunotherapy paradigm. Cancer Immunol Immunother 64, 299–309 (2015). https://doi.org/10.1007/s00262-014-1622-z

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  • DOI: https://doi.org/10.1007/s00262-014-1622-z

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