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The roles of thermal and mechanical stress in focused ultrasound-mediated immunomodulation and immunotherapy for central nervous system tumors

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Abstract

Background

Focused ultrasound (FUS) is an emerging technology, offering the capability of tuning and prescribing thermal and mechanical treatments within the brain. While early works in utilizing this technology have mainly focused on maximizing the delivery of therapeutics across the blood–brain barrier (BBB), the potential therapeutic impact of FUS-induced controlled thermal and mechanical stress to modulate anti-tumor immunity is becoming increasingly recognized.

Objective

To better understand the roles of FUS-mediated thermal and mechanical stress in promoting anti-tumor immunity in central nervous system tumors, we performed a comprehensive literature review on focused ultrasound-mediated immunomodulation and immunotherapy in brain tumors.

Methods

First, we summarize the current clinical experience with immunotherapy. Then, we discuss the unique and distinct immunomodulatory effects of the FUS-mediated thermal and mechanical stress in the brain tumor-immune microenvironment. Finally, we highlight recent findings that indicate that its combination with immune adjuvants can promote robust responses in brain tumors.

Results

Along with the rapid advancement of FUS technologies into recent clinical trials, this technology through mild-hyperthermia, thermal ablation, mechanical perturbation mediated by microbubbles, and histotripsy each inducing distinct vascular and immunological effects, is offering the unique opportunity to improve immunotherapeutic trafficking and convert immunologically “cold” tumors into immunologically “hot” ones that are prone to generate prolonged anti-tumor immune responses.

Conclusions

While FUS technology is clearly accelerating concepts for new immunotherapeutic combinations, additional parallel efforts to detail rational therapeutic strategies supported by rigorous preclinical studies are still in need to leverage potential synergies of this technology with immune adjuvants. This work will accelerate the discovery and clinical implementation of new effective FUS immunotherapeutic combinations for brain tumor patients.

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Data Availability

All the associated data in this review paper are included in the paper (Tables) or can be found in the cited literature.

References

  1. Meng Y, Hynynen K, Lipsman N (2021) Applications of focused ultrasound in the brain: from thermoablation to drug delivery. Nat Rev Neurol 17:7–22. https://doi.org/10.1038/s41582-020-00418-z

    Article  PubMed  Google Scholar 

  2. ter Haar >Gail, Coussios C, (2007) High intensity focused ultrasound: Physical principles and devices. Int J Hyperthermia 23:89–104. https://doi.org/10.1080/02656730601186138

    Article  Google Scholar 

  3. ter Haar G (2007) Therapeutic applications of ultrasound. Prog Biophys Mol Biol 93:111–129

    Article  PubMed  Google Scholar 

  4. McDannold N, Clement GT, Black P et al (2010) Transcranial magnetic resonance imaging- guided focused ultrasound surgery of brain tumors: initial findings in 3 patients. Neurosurgery 66:323–332

    Article  PubMed  Google Scholar 

  5. Elias WJ, Huss D, Voss T et al (2013) A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med 369:640–648. https://doi.org/10.1056/NEJMoa1300962

    Article  CAS  PubMed  Google Scholar 

  6. Elias WJ, Lipsman N, Ondo WG et al (2016) A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med 375:730–739. https://doi.org/10.1056/NEJMoa1600159

    Article  PubMed  Google Scholar 

  7. Martínez-Fernández R, Máñez-Miró JU, Rodríguez-Rojas R et al (2020) Randomized trial of focused ultrasound subthalamotomy for parkinson’s disease. N Engl J Med 383:2501–2513. https://doi.org/10.1056/NEJMoa2016311

    Article  PubMed  Google Scholar 

  8. Song K-H, Harvey BK, Borden MA (2018) State-of-the-art of microbubble-assisted blood-brain barrier disruption. Theranostics 8:4393–4408. https://doi.org/10.7150/thno.26869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dauba A, Delalande A, Kamimura HAS et al (2020) Recent advances on ultrasound contrast agents for blood-brain barrier opening with focused ultrasound. Pharmaceutics 12:1125. https://doi.org/10.3390/pharmaceutics12111125

    Article  CAS  PubMed Central  Google Scholar 

  10. Stride E, Coussios C (2019) Nucleation, mapping and control of cavitation for drug delivery. Nat Rev Phys. https://doi.org/10.1038/s42254-019-0074-y

    Article  Google Scholar 

  11. Aryal M, Arvanitis CD, Alexander PM, McDannold N (2014) Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system. Adv Drug Deliv Rev 72:94–109. https://doi.org/10.1016/j.addr.2014.01.008

    Article  CAS  PubMed  Google Scholar 

  12. Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA (2001) Noninvasive MR imaging–guided focal opening of the blood-brain barrier in rabbits1. Radiology 220:640–646. https://doi.org/10.1148/radiol.2202001804

    Article  CAS  PubMed  Google Scholar 

  13. Meairs S (2015) Facilitation of drug transport across the blood-brain barrier with ultrasound and microbubbles. Pharmaceutics 7:275–293. https://doi.org/10.3390/pharmaceutics7030275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schoen S, Kilinc MS, Lee H et al (2022) Towards controlled drug delivery in brain tumors with microbubble-enhanced focused ultrasound. Adv Drug Deliv Rev 180:114043. https://doi.org/10.1016/j.addr.2021.114043

    Article  CAS  PubMed  Google Scholar 

  15. Carpentier A, Canney M, Vignot A et al (2016) Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med 8:3432. https://doi.org/10.1126/scitranslmed.aaf6086

    Article  CAS  Google Scholar 

  16. Mainprize T, Lipsman N, Huang Y et al (2019) Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. Sci Rep 9:321. https://doi.org/10.1038/s41598-018-36340-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lipsman N, Meng Y, Bethune AJ et al (2018) Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun 9:2336. https://doi.org/10.1038/s41467-018-04529-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Idbaih A, Canney M, Belin L et al (2019) Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma. Clin Cancer Res Clincanres. https://doi.org/10.1158/1078-0432.CCR-18-3643

    Article  Google Scholar 

  19. Miller MW, Miller DL, Brayman AA (1996) A review of in vitro bioeffects of inertial ultrasonic cavitation from a mechanistic perspective. Ultrasound Med Biol 22:1131–1154. https://doi.org/10.1016/S0301-5629(96)00089-0

    Article  CAS  PubMed  Google Scholar 

  20. Cleve S, Inserra C, Prentice P (2019) Contrast Agent Microbubble Jetting during Initial Interaction with 200-kHz Focused Ultrasound. Ultrasound Med Biol 45:3075–3080. https://doi.org/10.1016/j.ultrasmedbio.2019.08.005

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chen H, Kreider W, Brayman AA et al (2011) Blood vessel deformations on microsecond time scales by ultrasonic cavitation. Phys Rev Lett 106:034301. https://doi.org/10.1103/PhysRevLett.106.034301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Todd N, Angolano C, Ferran C et al (2020) Secondary effects on brain physiology caused by focused ultrasound-mediated disruption of the blood–brain barrier. J Controlled Release 324:450–459. https://doi.org/10.1016/j.jconrel.2020.05.040

    Article  CAS  Google Scholar 

  23. McMahon D, O’Reilly MA, Hynynen K (2021) Therapeutic agent delivery across the blood-brain barrier using focused ultrasound. Annu Rev Biomed Eng. https://doi.org/10.1146/annurev-bioeng-062117-121238

    Article  PubMed  Google Scholar 

  24. McMahon D, Hynynen K (2017) Acute inflammatory response following increased blood-brain barrier permeability induced by focused ultrasound is dependent on microbubble dose. Theranostics 7:3989–4000. https://doi.org/10.7150/thno.21630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kovacs ZI, Kim S, Jikaria N et al (2016) Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation. Proc Natl Acad Sci. https://doi.org/10.1073/pnas.1614777114

    Article  PubMed  PubMed Central  Google Scholar 

  26. Arvanitis CD, Livingstone MS, Vykhodtseva N, McDannold N (2012) Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring. PLoS ONE 7:e45783. https://doi.org/10.1371/journal.pone.0045783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Baseri B, Choi JJ, Tung Y-S, Konofagou EE (2010) Multi-modality safety assessment of blood-brain barrier opening using focused ultrasound and definity microbubbles: a short-term study. Ultrasound Med Biol 36:1445–1459. https://doi.org/10.1016/j.ultrasmedbio.2010.06.005

    Article  PubMed  PubMed Central  Google Scholar 

  28. McMahon D, Lassus A, Gaud E et al (2020) Microbubble formulation influences inflammatory response to focused ultrasound exposure in the brain. Sci Rep 10:21534. https://doi.org/10.1038/s41598-020-78657-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Arvanitis CD, Vykhodtseva N, Jolesz F et al (2015) Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model. J Neurosurg 124:1450–1459. https://doi.org/10.3171/2015.4.JNS142862

    Article  PubMed  PubMed Central  Google Scholar 

  30. McDannold N, Zhang Y, Vykhodtseva N (2016) Nonthermal ablation in the rat brain using focused ultrasound and an ultrasound contrast agent: long-term effects. J Neurosurg 125:1539–1548. https://doi.org/10.3171/2015.10.JNS151525

    Article  PubMed  PubMed Central  Google Scholar 

  31. Peng C, Sun T, Vykhodtseva N et al (2019) Intracranial non-thermal ablation mediated by transcranial focused ultrasound and phase-shift nanoemulsions. Ultrasound Med Biol 45:2104–2117. https://doi.org/10.1016/j.ultrasmedbio.2019.04.010

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sukovich JR, Cain CA, Pandey AS et al (2018) In vivo histotripsy brain treatment. J Neurosurg. https://doi.org/10.3171/2018.4.JNS172652

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hendricks-Wenger A, Hutchison R, Vlaisavljevich E, Allen IC (2021) Immunological effects of histotripsy for cancer therapy. Front Oncol 11:681629. https://doi.org/10.3389/fonc.2021.681629

    Article  PubMed  PubMed Central  Google Scholar 

  34. Anastasiadis P, Gandhi D, Guo Y, Ahmed A-K, Bentzen SM, Arvanitis C, Woodworth GF (2021) Localized blood–brain barrier opening in infiltrating gliomas with MRI-guided acoustic emissions–controlled focused ultrasound. Proc Natl Acad Sci 118(37):e2103280118. https://doi.org/10.1073/pnas.2103280118

  35. Kim C, Guo Y, Leisen J et al (2021) Closed-loop trans-skull ultrasound hyperthermia leads to improved drug delivery from thermosensitive drugs and promotes changes in vascular transport dynamics in brain tumors. Theranostics 11:18

    Google Scholar 

  36. McDannold N, Vykhodtseva N, Jolesz FA, Hynynen K (2004) MRI investigation of the threshold for thermally induced blood-brain barrier disruption and brain tissue damage in the rabbit brain. Magn Reson Med 51:913–923. https://doi.org/10.1002/mrm.20060

    Article  PubMed  Google Scholar 

  37. Sabbagh A, Beccaria K, Ling X et al (2021) Opening of the blood-brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-20-3760

    Article  PubMed  PubMed Central  Google Scholar 

  38. Alkins R, Burgess A, Ganguly M et al (2013) Focused ultrasound delivers targeted immune cells to metastatic brain tumors. Cancer Res 73:1892–1899. https://doi.org/10.1158/0008-5472.CAN-12-2609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sampson JH, Gunn MD, Fecci PE, Ashley DM (2020) Brain immunology and immunotherapy in brain tumours. Nat Rev Cancer 20:12–25. https://doi.org/10.1038/s41568-019-0224-7

    Article  CAS  PubMed  Google Scholar 

  40. Engelhardt B, Ransohoff RM (2012) Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol 33:579–589. https://doi.org/10.1016/j.it.2012.07.004

    Article  CAS  PubMed  Google Scholar 

  41. Schläger C, Körner H, Krueger M et al (2016) Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature 530:349–353. https://doi.org/10.1038/nature16939

    Article  CAS  PubMed  Google Scholar 

  42. Tawbi HA, Forsyth PA, Algazi A et al (2018) Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 379:722–730. https://doi.org/10.1056/NEJMoa1805453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Long GV, Atkinson V, Lo S et al (2018) Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 19:672–681. https://doi.org/10.1016/S1470-2045(18)30139-6

    Article  CAS  PubMed  Google Scholar 

  44. Zeng J, See AP, Phallen J et al (2013) Anti-PD-1 Blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol 86:343–349. https://doi.org/10.1016/j.ijrobp.2012.12.025

    Article  CAS  Google Scholar 

  45. Filley AC, Henriquez M, Dey M (2017) Recurrent glioma clinical trial, CheckMate-143: the game is not over yet. Oncotarget 8:91779–91794. https://doi.org/10.18632/oncotarget.21586

    Article  PubMed  PubMed Central  Google Scholar 

  46. Reardon DA, Brandes AA, Omuro A et al (2020) Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma. JAMA Oncol 6:1–8. https://doi.org/10.1001/jamaoncol.2020.1024

    Article  PubMed Central  Google Scholar 

  47. Cloughesy TF, Mochizuki AY, Orpilla JR et al (2019) Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med 25:477–486. https://doi.org/10.1038/s41591-018-0337-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R et al (2019) Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med 25:470–476. https://doi.org/10.1038/s41591-018-0339-5

    Article  CAS  PubMed  Google Scholar 

  49. O’Rourke DM, Nasrallah M, Morrissette JJ et al (2016) Pilot study of T cells redirected to EGFRvIII with a chimeric antigen receptor in patients with EGFRvIII+ glioblastoma. J Clin Oncol 34:2067–2067. https://doi.org/10.1200/JCO.2016.34.15_suppl.2067

    Article  Google Scholar 

  50. Brown CE, Alizadeh D, Starr R et al (2016) Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med 375:2561–2569. https://doi.org/10.1056/NEJMoa1610497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ahmed N, Brawley V, Hegde M et al (2017) HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol 3:1094–1101. https://doi.org/10.1001/jamaoncol.2017.0184

    Article  PubMed  PubMed Central  Google Scholar 

  52. Majzner RG, Ramakrishna S, Yeom KW et al (2022) GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature. https://doi.org/10.1038/s41586-022-04489-4

    Article  PubMed  PubMed Central  Google Scholar 

  53. Arvanitis CD, Ferraro GB, Jain RK (2020) The blood–brain barrier and blood–tumour barrier in brain tumours and metastases. Nat Rev Cancer 20:26–41. https://doi.org/10.1038/s41568-019-0205-x

    Article  CAS  PubMed  Google Scholar 

  54. Sarkaria JN, Hu LS, Parney IF et al (2018) Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro-Oncol 20:184–191. https://doi.org/10.1093/neuonc/nox175

    Article  CAS  PubMed  Google Scholar 

  55. Phoenix TN, Patmore DM, Boop S et al (2016) Medulloblastoma genotype dictates blood brain barrier phenotype. Cancer Cell 29:508–522. https://doi.org/10.1016/j.ccell.2016.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vanan MI, Eisenstat DD (2015) DIPG in children – what can we learn from the past? Front Oncol. https://doi.org/10.3389/fonc.2015.00237

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lim M, Xia Y, Bettegowda C, Weller M (2018) Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol 15:422–442. https://doi.org/10.1038/s41571-018-0003-5

    Article  CAS  PubMed  Google Scholar 

  58. Rao G, Latha K, Ott M et al (2020) Anti–PD-1 Induces M1 Polarization in the glioma microenvironment and exerts therapeutic efficacy in the absence of CD8 Cytotoxic T Cells. Clin Cancer Res 26:4699–4712. https://doi.org/10.1158/1078-0432.CCR-19-4110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gordon SR, Maute RL, Dulken BW et al (2017) PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545:495–499. https://doi.org/10.1038/nature22396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Morad G, Helmink BA, Sharma P, Wargo JA (2021) Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. https://doi.org/10.1016/j.cell.2021.09.020

    Article  PubMed  Google Scholar 

  61. Postow MA, Sidlow R, Hellmann MD (2018) Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378:158–168. https://doi.org/10.1056/NEJMra1703481

    Article  CAS  PubMed  Google Scholar 

  62. Thorsson V, Gibbs DL, Brown SD et al (2018) The immune landscape of cancer. Immunity 48:812-830.e14. https://doi.org/10.1016/j.immuni.2018.03.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Brown CE, Aguilar B, Starr R et al (2018) Optimization of IL13Rα2-targeted chimeric antigen receptor T cells for improved anti-tumor efficacy against glioblastoma. Mol Ther 26:31–44. https://doi.org/10.1016/j.ymthe.2017.10.002

    Article  CAS  PubMed  Google Scholar 

  64. Srinivasan ES, Sankey EW, Grabowski MM et al (2020) The intersection between immunotherapy and laser interstitial thermal therapy: a multipronged future of neuro-oncology. Int J Hyperthermia 37:27–34. https://doi.org/10.1080/02656736.2020.1746413

    Article  CAS  PubMed  Google Scholar 

  65. Jackson CM, Kochel CM, Nirschl CJ et al (2016) Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination. Clin Cancer Res Off J Am Assoc Cancer Res 22:1161–1172. https://doi.org/10.1158/1078-0432.CCR-15-1516

    Article  CAS  Google Scholar 

  66. Fukumura D, Kloepper J, Amoozgar Z et al (2018) Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 15:325–340. https://doi.org/10.1038/nrclinonc.2018.29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Quail DF, Joyce JA (2017) The Microenvironmental Landscape of Brain Tumors. Cancer Cell 31:326–341. https://doi.org/10.1016/j.ccell.2017.02.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Stoklasek TA, Schluns KS, Lefrancois L (2006) Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J Immunol 177:6072–6080

    Article  CAS  PubMed  Google Scholar 

  69. Stephan MT, Moon JJ, Um SH et al (2010) Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat Med 16:1035–1041. https://doi.org/10.1038/nm.2198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dubois S, Patel HJ, Zhang M et al (2008) Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. J Immunol 180:2099–2106

    Article  CAS  PubMed  Google Scholar 

  71. Rubinstein MP, Kovar M, Purton JF et al (2006) Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci U A 103:9166–9171. https://doi.org/10.1073/pnas.0600240103

    Article  CAS  Google Scholar 

  72. Waldmann TA (2006) The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 6:595–601. https://doi.org/10.1038/nri1901

    Article  CAS  PubMed  Google Scholar 

  73. Kaehler KC, Piel S, Livingstone E et al (2010) Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. Semin Oncol 37:485–498. https://doi.org/10.1053/j.seminoncol.2010.09.003

    Article  CAS  PubMed  Google Scholar 

  74. Kovacs ZI, Kim S, Jikaria N et al (2017) Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation. Proc Natl Acad Sci U S A 114:E75–E84. https://doi.org/10.1073/pnas.1614777114

    Article  CAS  PubMed  Google Scholar 

  75. Poon C, Pellow C, Hynynen K (2021) Neutrophil recruitment and leukocyte response following focused ultrasound and microbubble mediated blood-brain barrier treatments. Theranostics 11:1655–1671. https://doi.org/10.7150/thno.52710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sinharay S, Tu T-W, Kovacs ZI et al (2019) In vivo imaging of sterile microglial activation in rat brain after disrupting the blood-brain barrier with pulsed focused ultrasound: [18F]DPA-714 PET study. J Neuroinflammation 16:155. https://doi.org/10.1186/s12974-019-1543-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Curley CT, Stevens AD, Mathew AS et al (2020) Immunomodulation of intracranial melanoma in response to blood-tumor barrier opening with focused ultrasound. Theranostics 10:8821–8833. https://doi.org/10.7150/thno.47983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chen P-Y, Hsieh H-Y, Huang C-Y et al (2015) Focused ultrasound-induced blood-brain barrier opening to enhance interleukin-12 delivery for brain tumor immunotherapy: a preclinical feasibility study. J Transl Med 13:93. https://doi.org/10.1186/s12967-015-0451-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kovacs Z, Werner B, Rassi A et al (2014) Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models. J Controlled Release 187:74–82. https://doi.org/10.1016/j.jconrel.2014.05.033

    Article  CAS  Google Scholar 

  80. Liu H-L, Hua M-Y, Chen P-Y et al (2010) Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology 255:415–425. https://doi.org/10.1148/radiol.10090699

    Article  PubMed  Google Scholar 

  81. Liu H-L, Huang C-Y, Chen J-Y et al (2014) Pharmacodynamic and Therapeutic Investigation of Focused Ultrasound-Induced Blood-Brain Barrier Opening for Enhanced Temozolomide Delivery in Glioma Treatment. PLoS ONE. https://doi.org/10.1371/journal.pone.0114311

    Article  PubMed  PubMed Central  Google Scholar 

  82. Sheybani ND, Breza VR, Paul S et al (2021) ImmunoPET-informed sequence for focused ultrasound-targeted mCD47 blockade controls glioma. J Controlled Release 331:19–29. https://doi.org/10.1016/j.jconrel.2021.01.023

    Article  CAS  Google Scholar 

  83. Treat LH, McDannold N, Zhang Y et al (2012) Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma. Ultrasound Med Biol 38:1716–1725. https://doi.org/10.1016/j.ultrasmedbio.2012.04.015

    Article  PubMed  PubMed Central  Google Scholar 

  84. Wei H-J, Upadhyayula PS, Pouliopoulos AN et al (2021) Focused Ultrasound-mediated blood-brain barrier opening increases delivery and efficacy of etoposide for glioblastoma treatment. Int J Radiat Oncol 110:539–550. https://doi.org/10.1016/j.ijrobp.2020.12.019

    Article  Google Scholar 

  85. Zhao G, Huang Q, Wang F et al (2018) Targeted shRNA-loaded liposome complex combined with focused ultrasound for blood brain barrier disruption and suppressing glioma growth. Cancer Lett 418:147–158. https://doi.org/10.1016/j.canlet.2018.01.035

    Article  CAS  PubMed  Google Scholar 

  86. Joiner JB, Pylayeva-Gupta Y (1950) Dayton PA (2020) Focused ultrasound for immunomodulation of the tumor microenvironment. J Immunol Baltim Md 205:2327–2341. https://doi.org/10.4049/jimmunol.1901430

    Article  CAS  Google Scholar 

  87. Eranki A, Srinivasan P, Ries M et al (2020) High-intensity focused Ultrasound (HIFU) triggers immune sensitization of refractory murine neuroblastoma to checkpoint inhibitor therapy. Clin Cancer Res Off J Am Assoc Cancer Res 26:1152–1161. https://doi.org/10.1158/1078-0432.CCR-19-1604

    Article  CAS  Google Scholar 

  88. Khokhlova V, Fowlkes J, Roberts W et al (2015) Histotripsy methods in mechanical disintegration of tissue: toward clinical applications. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group 31:145–162. https://doi.org/10.3109/02656736.2015.1007538

    Article  Google Scholar 

  89. Hu Z, Yang XY, Liu Y et al (2007) Investigation of HIFU-induced anti-tumor immunity in a murine tumor model. J Transl Med 5:34. https://doi.org/10.1186/1479-5876-5-34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Huang X, Yuan F, Liang M et al (2012) M-HIFU inhibits tumor growth, suppresses STAT3 activity and enhances tumor specific immunity in a transplant tumor model of prostate cancer. PLoS ONE 7:e41632. https://doi.org/10.1371/journal.pone.0041632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Qu S, Worlikar T, Felsted AE et al (2020) Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy. J Immunother Cancer 8:e000200. https://doi.org/10.1136/jitc-2019-000200

    Article  PubMed  PubMed Central  Google Scholar 

  92. Schade GR, Wang Y-N, D’Andrea S et al (2019) Boiling histotripsy ablation of renal cell carcinoma in the EKER rat promotes a systemic inflammatory response. Ultrasound Med Biol 45:137–147. https://doi.org/10.1016/j.ultrasmedbio.2018.09.006

    Article  PubMed  Google Scholar 

  93. Mathew AS, Gorick CM, Thim EA et al (2020) Transcriptomic response of brain tissue to focused ultrasound-mediated blood–brain barrier disruption depends strongly on anesthesia. Bioeng Transl Med 6:e10198. https://doi.org/10.1002/btm2.10198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gorick CM, Mathew AS, Garrison WJ et al (2020) Sonoselective transfection of cerebral vasculature without blood–brain barrier disruption. Proc Natl Acad Sci 117:5644–5654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. McMahon D, Bendayan R, Hynynen K (2017) Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome. Sci Rep 7:45657. https://doi.org/10.1038/srep45657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kovacs ZI, Tu T-W, Sundby M et al (2018) MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain. Theranostics 8:4837–4855. https://doi.org/10.7150/thno.24512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rao G, Latha K, Ott M et al (2020) Anti-PD-1 induces M1 polarization in the glioma microenvironment and exerts therapeutic efficacy in the absence of CD8 cytotoxic t cells. Clin Cancer Res Off J Am Assoc Cancer Res 26:4699–4712. https://doi.org/10.1158/1078-0432.CCR-19-4110

    Article  CAS  Google Scholar 

  98. Ilovitsh T, Feng Y, Foiret J et al (2020) Low-frequency ultrasound-mediated cytokine transfection enhances T cell recruitment at local and distant tumor sites. Proc Natl Acad Sci 117:12674–12685. https://doi.org/10.1073/pnas.1914906117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wang J, Huang C-H, Echeagaray OH et al (2019) Microshell enhanced acoustic adjuvants for immunotherapy in glioblastoma. Adv Ther 2:1900066. https://doi.org/10.1002/adtp.201900066

    Article  CAS  Google Scholar 

  100. Alkins R, Burgess A, Kerbel R et al (2016) Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival. Neuro-Oncol 18:974–981. https://doi.org/10.1093/neuonc/nov318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kovacs ZI, Burks SR, Frank JA (2018) Focused ultrasound with microbubbles induces sterile inflammatory response proportional to the blood brain barrier opening: Attention to experimental conditions. Theranostics 8:2245–2248. https://doi.org/10.7150/thno.24181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Guo Y, Lee H, Fang Z et al (2021) Single-cell analysis reveals effective siRNA delivery in brain tumors with microbubble-enhanced ultrasound and cationic nanoparticles. Sci Adv 7:7390. https://doi.org/10.1126/sciadv.abf7390

    Article  CAS  Google Scholar 

  103. Zhang N, Wang J, Foiret J et al (2021) Synergies between therapeutic ultrasound, gene therapy and immunotherapy in cancer treatment. Adv Drug Deliv Rev 178:113906. https://doi.org/10.1016/j.addr.2021.113906

    Article  CAS  PubMed  Google Scholar 

  104. Dewhirst MW, Lee C-T, Ashcraft KA (2016) The future of biology in driving the field of hyperthermia. Int J Hyperthermia 32:4–13. https://doi.org/10.3109/02656736.2015.1091093

    Article  PubMed  Google Scholar 

  105. Hersh DS, Kim AJ, Winkles JA et al (2016) Emerging applications of therapeutic ultrasound in neuro-oncology: moving beyond tumor ablation. Neurosurgery 79:643–654. https://doi.org/10.1227/NEU.0000000000001399

    Article  PubMed  Google Scholar 

  106. Kennedy JE (2005) High-intensity focused ultrasound in the treatment of solid tumours. Nat Rev Cancer 5:321. https://doi.org/10.1038/nrc1591

    Article  CAS  PubMed  Google Scholar 

  107. Cuenod CA, Balvay D (2013) Perfusion and vascular permeability: basic concepts and measurement in DCE-CT and DCE-MRI. Diagn Interv Imaging 94:1187–1204. https://doi.org/10.1016/j.diii.2013.10.010

    Article  CAS  PubMed  Google Scholar 

  108. Csoboz B, Balogh GE, Kusz E et al (2013) Membrane fluidity matters: hyperthermia from the aspects of lipids and membranes. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group 29:491–499. https://doi.org/10.3109/02656736.2013.808765

    Article  CAS  Google Scholar 

  109. Watson KD, Lai C-Y, Qin S et al (2012) Ultrasound increases nanoparticle delivery by reducing intratumoral pressure and increasing transport in epithelial and epithelial-mesenchymal transition tumors. Cancer Res 72:1485–1493. https://doi.org/10.1158/0008-5472.CAN-11-3232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Skitzki JJ, Repasky EA (2000) Evans SS (2009) Hyperthermia as an immunotherapy strategy for cancer. Curr Opin Investig Drugs Lond Engl 10:550–558

    Google Scholar 

  111. Skandalakis GP, Rivera DR, Rizea CD et al (2020) Hyperthermia treatment advances for brain tumors. Int J Hyperthermia 37:3–19. https://doi.org/10.1080/02656736.2020.1772512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Frey B, Weiss E-M, Rubner Y et al (2012) Old and new facts about hyperthermia-induced modulations of the immune system. Int J Hyperthermia 28:528–542. https://doi.org/10.3109/02656736.2012.677933

    Article  CAS  PubMed  Google Scholar 

  113. Santos MA, Wu S-K, Regenold M et al (2020) Novel fractionated ultrashort thermal exposures with MRI-guided focused ultrasound for treating tumors with thermosensitive drugs. Sci Adv 6:5684. https://doi.org/10.1126/sciadv.aba5684

    Article  CAS  Google Scholar 

  114. Liu H-L, Hsu P-H, Lin C-Y et al (2016) Focused ultrasound enhances central nervous system delivery of bevacizumab for malignant glioma treatment. Radiology 281:99–108. https://doi.org/10.1148/radiol.2016152444

    Article  PubMed  Google Scholar 

  115. Chen P-Y, Hsieh H-Y, Huang C-Y et al (2015) Focused ultrasound-induced blood–brain barrier opening to enhance interleukin-12 delivery for brain tumor immunotherapy: a preclinical feasibility study. J Transl Med 13:93. https://doi.org/10.1186/s12967-015-0451-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kobus T, Zervantonakis IK, Zhang Y, McDannold NJ (2016) Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption. J Control Release Off J Control Release Soc 238:281–288. https://doi.org/10.1016/j.jconrel.2016.08.001

    Article  CAS  Google Scholar 

  117. Deng J, Zhang Y, Feng J, Wu F (2010) Dendritic Cells Loaded with Ultrasound-Ablated Tumour Induce in vivo Specific Antitumour Immune Responses. Ultrasound Med Biol 36:441–448. https://doi.org/10.1016/j.ultrasmedbio.2009.12.004

    Article  PubMed  Google Scholar 

  118. Silvestrini MT, Ingham ES, Mahakian LM et al (2017) Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols. JCI Insight 2:e90521. https://doi.org/10.1172/jci.insight.90521

    Article  PubMed  PubMed Central  Google Scholar 

  119. Chavez M, Silvestrini MT, Ingham ES et al (2018) Distinct immune signatures in directly treated and distant tumors result from TLR adjuvants and focal ablation. Theranostics 8:3611–3628. https://doi.org/10.7150/thno.25613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fite BZ, Wang J, Kare AJ et al (2021) Immune modulation resulting from MR-guided high intensity focused ultrasound in a model of murine breast cancer. Sci Rep 11:927. https://doi.org/10.1038/s41598-020-80135-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kheirolomoom A, Silvestrini MT, Ingham ES et al (2019) Combining activatable nanodelivery with immunotherapy in a murine breast cancer model. J Control Release Off J Control Release Soc 303:42–54. https://doi.org/10.1016/j.jconrel.2019.04.008

    Article  CAS  Google Scholar 

  122. Sheybani ND, Witter AR, Thim EA et al (2020) Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity. J Immunother Cancer 8:e001008. https://doi.org/10.1136/jitc-2020-001008

    Article  PubMed  PubMed Central  Google Scholar 

  123. Curley CT, Sheybani ND, Bullock TN, Price RJ (2017) Focused Ultrasound immunotherapy for central nervous system pathologies: challenges and opportunities. Theranostics 7:3608–3623. https://doi.org/10.7150/thno.21225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Shin DH, Melnick KF, Tran DD, Ghiaseddin AP (2021) In situ vaccination with laser interstitial thermal therapy augments immunotherapy in malignant gliomas. J Neurooncol 151:85–92. https://doi.org/10.1007/s11060-020-03557-x

    Article  PubMed  Google Scholar 

  125. van den Bijgaart RJ, E, Eikelenboom DC, et al (2017) Thermal and mechanical high-intensity focused ultrasound: perspectives on tumor ablation, immune effects and combination strategies. Cancer Immunol Immunother 66:247–258. https://doi.org/10.1007/s00262-016-1891-9

    Article  PubMed  Google Scholar 

  126. Bredlau AL, Motamarry A, Chen C et al (2018) Localized delivery of therapeutic doxorubicin dose across the canine blood–brain barrier with hyperthermia and temperature sensitive liposomes. Drug Deliv 25:973–984. https://doi.org/10.1080/10717544.2018.1461280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Salehi A, Paturu MR, Patel B et al (2020) Therapeutic enhancement of blood–brain and blood–tumor barriers permeability by laser interstitial thermal therapy. Neuro-Oncol Adv. https://doi.org/10.1093/noajnl/vdaa071

    Article  Google Scholar 

  128. Lu P, Zhu X-Q, Xu Z-L et al (2009) Increased infiltration of activated tumor-infiltrating lymphocytes after high intensity focused ultrasound ablation of human breast cancer. Surgery 145:286–293. https://doi.org/10.1016/j.surg.2008.10.010

    Article  PubMed  Google Scholar 

  129. Xu Z-L, Zhu X-Q, Lu P et al (2009) Activation of tumor-infiltrating antigen presenting cells by high intensity focused ultrasound ablation of human breast cancer. Ultrasound Med Biol 35:50–57. https://doi.org/10.1016/j.ultrasmedbio.2008.08.005

    Article  CAS  PubMed  Google Scholar 

  130. Zhou Q, Zhu X-Q, Zhang J et al (2008) Changes in circulating immunosuppressive cytokine levels of cancer patients after high intensity focused ultrasound treatment. Ultrasound Med Biol 34:81–87. https://doi.org/10.1016/j.ultrasmedbio.2007.07.013

    Article  CAS  PubMed  Google Scholar 

  131. Figueroa JM, Semonche A, Magoon S et al (2020) The role of neutrophil-to-lymphocyte ratio in predicting overall survival in patients undergoing laser interstitial thermal therapy for glioblastoma. J Clin Neurosci 72:108–113. https://doi.org/10.1016/j.jocn.2019.12.057

    Article  PubMed  Google Scholar 

  132. Liu F, Hu Z, Qiu L et al (2010) Boosting high-intensity focused ultrasound-induced anti-tumor immunity using a sparse-scan strategy that can more effectively promote dendritic cell maturation. J Transl Med 8:7. https://doi.org/10.1186/1479-5876-8-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Gamboa L, Zamat AH, Kwong GA (2020) Synthetic immunity by remote control Theranostics 10:3652–3667. https://doi.org/10.7150/thno.41305

    Article  CAS  PubMed  Google Scholar 

  134. Wu Y, Liu Y, Huang Z et al (2021) Control of the activity of CAR-T cells within tumours via focused ultrasound. Nat Biomed Eng. https://doi.org/10.1038/s41551-021-00779-w

    Article  PubMed  PubMed Central  Google Scholar 

  135. Meng Y, Pople CB, Budiansky D et al (2022) Current state of therapeutic focused ultrasound applications in neuro-oncology. J Neurooncol 156:49–59. https://doi.org/10.1007/s11060-021-03861-0

    Article  PubMed  Google Scholar 

  136. Schneider CS, Woodworth GF, Vujaskovic Z, Mishra MV (2020) Radiosensitization of high-grade gliomas through induced hyperthermia: Review of clinical experience and the potential role of MR-guided focused ultrasound. Radiother Oncol J Eur Soc Ther Radiol Oncol 142:43–51. https://doi.org/10.1016/j.radonc.2019.07.017

    Article  CAS  Google Scholar 

  137. Guthkelch AN, Carter LP, Cassady JR et al (1991) Treatment of malignant brain tumors with focused ultrasound hyperthermia and radiation: results of a phase I trial. J Neurooncol. https://doi.org/10.1007/BF00177540

    Article  PubMed  Google Scholar 

  138. White PJ, Zhang Y-Z, Power C et al (2020) Observed effects of whole-brain radiation therapy on focused ultrasound blood-brain barrier disruption. Ultrasound Med Biol 46:1998–2006. https://doi.org/10.1016/j.ultrasmedbio.2020.04.013

    Article  PubMed  PubMed Central  Google Scholar 

  139. Wang S, Wu C-C, Zhang H et al (2020) Focused ultrasound induced-blood–brain barrier opening in mouse brain receiving radiosurgery dose of radiation enhances local delivery of systemic therapy. Br J Radiol 93:20190214. https://doi.org/10.1259/bjr.20190214

    Article  PubMed  PubMed Central  Google Scholar 

  140. Shi J, Fu C, Su X et al (2021) Ultrasound-stimulated microbubbles inhibit aggressive phenotypes and promotes radiosensitivity of esophageal squamous cell carcinoma. Bioengineered 12:3000–3013. https://doi.org/10.1080/21655979.2021.1931641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Costas Arvanitis research in this area is supported by the NIH (National Institutes of Health) Grant R37CA239039 (National Cancer Institute) and the Ian’s Friends Foundation. Graeme Woodworth’s research in this area is supported by NIH Grant R21NS113016 and the Focused Ultrasound Foundation

Funding

Costas Arvanitis research in this area is supported by NIH Grant R37CA239039 and the Ian’s Friends Foundation. Graeme Woodworth’s research in this area is supported by NIH Grant R21NS113016 and the Focused Ultrasound Foundation.

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Authors and Affiliations

  1. School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA

    Chulyong Kim & Costas D. Arvanitis

  2. Department of Neurosurgery, School of Medicine (Oncology), of Neurology, of Otolaryngology, and of Radiation Oncology, Stanford University, Paulo Alto, CA, USA

    Michael Lim

  3. Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA

    Graeme F. Woodworth

  4. Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Graeme F. Woodworth

  5. Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA

    Graeme F. Woodworth

  6. Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA

    Costas D. Arvanitis

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Conceptualization: all authors; formal analysis and investigation: CK, CDA; writing—original draft preparation: CK, CDA; writing—review and editing: all authors.

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Correspondence to Costas D. Arvanitis.

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Kim, C., Lim, M., Woodworth, G.F. et al. The roles of thermal and mechanical stress in focused ultrasound-mediated immunomodulation and immunotherapy for central nervous system tumors. J Neurooncol 157, 221–236 (2022). https://doi.org/10.1007/s11060-022-03973-1

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