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Review
. 2016 Jan 22:4:2.
doi: 10.1186/s40349-016-0046-y. eCollection 2016.

Focused ultrasound-aided immunomodulation in glioblastoma multiforme: a therapeutic concept

Or Cohen-Inbar  1 , Zhiyuan Xu  2 , Jason P Sheehan  2
Affiliations
Review

Focused ultrasound-aided immunomodulation in glioblastoma multiforme: a therapeutic concept

Or Cohen-Inbar et al. J Ther Ultrasound. .

Abstract

Patients with glioblastoma multiforme (GBM) exhibit a deficient anti-tumor immune response. Both arms of the immune system were shown to be hampered in GBM, namely the local cellular immunity mediated by the Th1 subset of helper T cells and the systemic humoral immunity mediated by the Th2 subset of helper T cells. Immunotherapy is rapidly becoming one of the pillars of anti-cancer therapy. GBM has not received similar clinical successes as of yet, which may be attributed to its relative inaccessibility (the blood-brain barrier (BBB)), its poor immunogenicity, few characterized cancer antigens, or any of the many other immune mechanisms known to be hampered. Focused ultrasound (FUS) is emerging as a promising treatment approach. The effects of FUS on the tissue are not merely thermal. Mounting evidence suggests that in addition to thermal ablation, FUS induces mechanical acoustic cavitation and immunomodulation plays a key role in boosting the host anti-tumor immune responses. We separately discuss the different pertinent immunosuppressive mechanisms harnessed by GBM and the immunomodulatory effects of FUS. The effect of FUS and microbubbles in disrupting the BBB and introducing antigens and drugs to the tumor milieu is discussed. The FUS-induced pro-inflammatory cytokines secretion and stress response, the FUS-induced change in the intra-tumoral immune-cells populations, the FUS-induced augmentation of dendritic cells activity, and the FUS-induced increased cytotoxic cells potency are all discussed. We next attempt at offering a conceptual synopsis of the synergistic treatment of GBM utilizing FUS and immunotherapy. In conclusion, it is increasingly apparent that no single treatment modality will triumph on GBM. The reviewed FUS-induced immunomodulation effects can be harnessed to current and developing immunotherapy approaches. Together, these may overcome GBM-induced immune-evasion and generate a clinically relevant anti-tumor immune response.

Keywords: FUS; Focused ultrasound; GBM; HIFU; Immunomodulation; Synergistic immunotherapy.

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Figures

Fig. 1
Fig. 1
Synopsis. The key established mechanisms hampered in GBM and the key immune-modulating effects of HIFU are presented. A theoretical action-reaction scheme is presented, connecting certain known GBM-evasion mechanisms with the FUS-induced counter response. Note that a single FUS-induced effect may influence a multitude of immunosuppressive mechanisms and vice versa. Refer to text
See this image and copyright information in PMC

References

    1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96. doi: 10.1056/NEJMoa043330. - DOI - PubMed
    1. Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, et al. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol. 2014;15(9):e395–403. doi: 10.1016/S1470-2045(14)70011-7. - DOI - PubMed
    1. Or cohen-inbar. Focused Neurosurgery book. Jaypee Brothers Publishers, 2015.
    1. Krauze AV, Myrehaug SD, Chang MG, Holdford DJ, Smith S, Shih J, et al. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma. Int J Radiat Oncol Biol Phys. 2015;92(5):986–92. doi: 10.1016/j.ijrobp.2015.04.038. - DOI - PMC - PubMed
    1. Wainwright DA, Chang AL, Dey M, Balyasnikova IV, Kim CK, Tobias A, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res. 2014;20(20):5290–301. doi: 10.1158/1078-0432.CCR-14-0514. - DOI - PMC - PubMed