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Enhancement of glioma-specific immunity in mice by “NOBEL”, an insulin-like growth factor 1 receptor antisense oligodeoxynucleotide

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Abstract

Autologous glioblastoma multiforme tumor cells treated with an antisense oligodeoxynucleotide (AS-ODN) targeting insulin-like growth factor receptor-1 (IGF-1R) are the basis of a vaccine with therapeutic effects on tumor recurrence in a pilot clinical trial. As a preface to continued clinical investigation of this vaccination strategy, we have studied the contribution of an optimized IGF-1R AS-ODN, designated “NOBEL”, to the induction of immunity to mouse GL261 glioma cells. The impact of NOBEL on mechanisms contributing to the development of GL261 immunity was first examined in the periphery. GL261 cells are naturally immunogenic when implanted into the flanks of congenic C57BL/6 mice, immunizing rather than forming tumors in around 50 % of these animals but causing tumors in the majority of mice lacking T and B lymphocytes. Overnight treatment with NOBEL in vitro reduces IGF-1R expression by GL261 cells but has minimal effect on cell viability and does not reduce the capacity of the cells to form tumors upon implantation. In contrast, tumors are extremely rare when GL261 cells are mixed with NOBEL at inoculation into the flanks of C57BL/6, and the recipient mice become immune to subcutaneous and intracranial challenge with untreated GL261. Adaptive immune mechanisms contribute to this effect, as immunocompromised mice fail to either fully control tumor formation or develop immunity following flank administration of the GL261/NOBEL mix. NOBEL’s structure has known immunostimulatory motifs that likely contribute to the immunogenicity of the mix, but its specificity for IGF-1R mRNA is also important as a similarly structured sense molecule is not effective.

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Abbreviations

AS-ODN:

Antisense oligodeoxynucleotide

APC:

Antigen presenting cells

BBB:

Blood–brain barrier

B2M−/− :

Beta-2 microglobulin knockout (CD8 T deficient)

CELISA:

Cell-based ELISA

DLN:

Draining lymph nodes

ELISA:

Enzyme-linked immunosorbent assay

FBS:

Fetal bovine sera

GBM:

Glioblastoma multiforme

IGF-1R:

Insulin-like growth factor 1 receptor

JHD−/− :

Antibody heavy chain knockout (B cell deficient)

MFI:

Mean fluorescence intensity

NKT:

Natural killer T cells

PBS:

Phosphate-buffered saline

qRT-PCR:

Quantitative real-time polymerase chain reaction

Rag2−/− :

Recombination activating gene 2 knockout (T and B deficient)

TLR9:

Toll-like receptor 9

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Acknowledgments

The authors gratefully acknowledge technical support provided by Rhonda B. Kean and Emily Bongiorno. This work was funded by the generous support of the Albert F. Stevens Foundation through a grant to David W. Andrews.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Author notes

  1. Kirsten M. Hooper

    Present address: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA

Authors and Affiliations

  1. Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Mélanie Morin-Brureau, Kirsten M. Hooper, Sami Sauma, Larry A. Harshyne, David W. Andrews & D. Craig Hooper

  2. Department of Cancer Biology, Thomas Jefferson University, 1020 Locust Street, JAH Rm 452, Philadelphia, PA, 19107-6731, USA

    Michael Prosniak & D. Craig Hooper

Authors
  1. Mélanie Morin-Brureau
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Correspondence to D. Craig Hooper.

Additional information

Mélanie Morin-Brureau and Kirsten M. Hooper made equal contributions to this work.

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Morin-Brureau, M., Hooper, K.M., Prosniak, M. et al. Enhancement of glioma-specific immunity in mice by “NOBEL”, an insulin-like growth factor 1 receptor antisense oligodeoxynucleotide. Cancer Immunol Immunother 64, 447–457 (2015). https://doi.org/10.1007/s00262-015-1654-z

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  • DOI: https://doi.org/10.1007/s00262-015-1654-z

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