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Advances in local therapy for glioblastoma — taking the fight to the tumour

Abstract

Despite advances in neurosurgery, chemotherapy and radiotherapy, glioblastoma remains one of the most treatment-resistant CNS malignancies, and the tumour inevitably recurs. The majority of recurrences appear in or near the resection cavity, usually within the area that received the highest dose of radiation. Many new therapies focus on combatting these local recurrences by implementing treatments directly in or near the tumour bed. In this Review, we discuss the latest developments in local therapy for glioblastoma, focusing on recent preclinical and clinical trials. The approaches that we discuss include novel intraoperative techniques, various treatments of the surgical cavity, stereotactic injections directly into the tumour, and new developments in convection-enhanced delivery and intra-arterial treatments.

Key points

  • Glioblastoma almost always recurs at or near the resection cavity, within the radiotherapy field.

  • Local therapy provides a unique opportunity to deliver high doses of therapeutics to the area with the highest concentration of glioblastoma cells, with limited systemic adverse effects.

  • Many phase I and II trials experimenting with various forms of local therapy have been — and are being — conducted in glioblastoma, with many showing great potential for improving progression-free and overall survival.

  • Large randomized phase III trials comparing local therapies with standard of care have been hindered by high cost, labour intensity and challenges in patient recruitment.

  • Close collaboration between clinicians, researchers, companies and governmental institutions is needed to smooth the transition from laboratory to phase I and II trials to large-scale randomized controlled trials.

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Fig. 1: Methods of local treatment in glioblastoma.
Fig. 2: Tumour cavity treatments for glioblastoma.
Fig. 3: Mechanisms of local viral therapies in development for glioblastoma.

References

  1. Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).

    CAS  PubMed  Google Scholar 

  2. Zhu, P., Du, X. L., Lu, G. & Zhu, J. J. Survival benefit of glioblastoma patients after FDA approval of temozolomide concomitant with radiation and bevacizumab: a population-based study. Oncotarget 8, 44015–44031 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. Stupp, R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459–466 (2009).

    CAS  PubMed  Google Scholar 

  4. Stupp, R. et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA 314, 2535–2543 (2015).

    CAS  PubMed  Google Scholar 

  5. Mittal, S. et al. Alternating electric tumor treating fields for treatment of glioblastoma: rationale, preclinical, and clinical studies. J. Neurosurg. 128, 414–421 (2018).

    CAS  PubMed  Google Scholar 

  6. Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 157, 753 (2014).

    CAS  Google Scholar 

  8. Broekman, M. L. et al. Multidimensional communication in the microenvirons of glioblastoma. Nat. Rev. Neurol. 14, 482–495 (2018).

    PubMed  PubMed Central  Google Scholar 

  9. Antunes, A. R. P. et al. Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies. eLife 9, e52176 (2020).

    CAS  Google Scholar 

  10. Jackson, M., Hassiotou, F. & Nowak, A. Glioblastoma stem-like cells: at the root of tumor recurrence and a therapeutic target. Carcinogenesis 36, 177–185 (2014).

    PubMed  Google Scholar 

  11. Brandes, A. A. et al. Recurrence pattern after temozolomide concomitant with and adjuvant to radiotherapy in newly diagnosed patients with glioblastoma: correlation with MGMT promoter methylation status. J. Clin. Oncol. 27, 1275–1279 (2009).

    CAS  PubMed  Google Scholar 

  12. McGirt, M. J. et al. Independent association of extent of resection with survival in patients with malignant brain astrocytoma: clinical article. J. Neurosurg. 110, 156–162 (2009).

    PubMed  Google Scholar 

  13. Duffau, H. Long-term outcomes after supratotal resection of diffuse low-grade gliomas: a consecutive series with 11-year follow-up. Acta Neurochir. 158, 51–58 (2016).

    PubMed  Google Scholar 

  14. De Leeuw, C. N. & Vogelbaum, M. A. Supratotal resection in glioma: a systematic review. Neuro Oncol. 21, 179–188 (2019).

    PubMed  Google Scholar 

  15. Titsworth, W. L., Murad, G. J. A., Hoh, B. L. & Rahman, M. Fighting fire with fire: the revival of thermotherapy for gliomas. Anticancer. Res. 34, 565–574 (2014).

    Google Scholar 

  16. Watanabe, M., Tanaka, R., Hondo, H. & Kuroki, M. Effects of antineoplastic agents and hyperthermia on cytotoxicity toward chronically hypoxic glioma cells. Int. J. Hyperthermia 8, 131–138 (1992).

    CAS  PubMed  Google Scholar 

  17. Menovsky, T., Beek, J. F., Van Gemert, M. J. C., Roux, F. X. & Bown, S. G. Interstitial laser thermotherapy in neurosurgery: a review. Acta Neurochir. 138, 1019–1026 (1996).

    CAS  PubMed  Google Scholar 

  18. Man, J. et al. Hyperthermia sensitizes glioma stem-like cells to radiation by inhibiting AKT signaling. Cancer Res. 75, 1760–1769 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Schildkopf, P. et al. Biological rationales and clinical applications of temperature controlled hyperthermia – implications for multimodal cancer treatments. Curr. Med. Chem. 17, 3045–3057 (2010).

    CAS  PubMed  Google Scholar 

  20. Frey, B. et al. Old and new facts about hyperthermia-induced modulations of the immune system. Int. J. Hyperthermia 28, 528–542 (2012).

    CAS  PubMed  Google Scholar 

  21. Lee, I., Kalkanis, S. & Hadjipanayis, C. G. Stereotactic laser interstitial thermal therapy for recurrent high-grade gliomas. Clin. Neurosurg. 79, S24–S34 (2016).

    Google Scholar 

  22. Holste, K. G. & Orringer, D. A. Laser interstitial thermal therapy. Neurooncol Adv. 2, vdz035 (2020).

    PubMed  Google Scholar 

  23. Mohammadi, A. M. et al. Upfront magnetic resonance imaging-guided stereotactic laser-ablation in newly diagnosed glioblastoma: a multicenter review of survival outcomes compared to a matched cohort of biopsy-only patients. Clin. Neurosurg. 85, 762–772 (2019).

    Google Scholar 

  24. Kamath, A. A. et al. Glioblastoma treated with magnetic resonance imaging-guided laser interstitial thermal therapy: safety, efficacy, and outcomes. Clin. Neurosurg. 84, 836–843 (2019).

    Google Scholar 

  25. Mohammadi, A. M. et al. The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study. Cancer Med. 3, 971–979 (2014).

    PubMed  PubMed Central  Google Scholar 

  26. Viozzi, I., Guberinic, A., Overduin, C. G., Rovers, M. M. & ter Laan, M. Laser interstitial thermal therapy in patients with newly diagnosed glioblastoma: a systematic review. J. Clin. Med. 10, 355 (2021).

    PubMed  PubMed Central  Google Scholar 

  27. Leuthardt, E. C., Voigt, J., Kim, A. H. & Sylvester, P. A single-center cost analysis of treating primary and metastatic brain cancers with either brain laser interstitial thermal therapy (LITT) or craniotomy. Pharmacoecon. Open 1, 53–63 (2017).

    PubMed  Google Scholar 

  28. Barnett, G. H., Voigt, J. D. & Alhuwalia, M. S. A systematic review and meta-analysis of studies examining the use of brain laser interstitial thermal therapy versus craniotomy for the treatment of high-grade tumors in or near areas of eloquence: an examination of the extent of resection and major complication rates associated with each type of surgery. Stereotact. Funct. Neurosurg. 94, 164–173 (2016).

    PubMed  Google Scholar 

  29. Maier-Hauff, K. et al. Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. J. Neurooncol. 103, 317–324 (2011).

    PubMed  Google Scholar 

  30. Grauer et al. Combined intracavitary thermotherapy with iron oxide nanoparticles and radiotherapy as local treatment modality in recurrent glioblastoma patients. J. Neurooncol. 141, 83–94 (2019).

    CAS  PubMed  Google Scholar 

  31. Brown, N. F., Carter, T. J., Ottaviani, D. & Mulholland, P. Harnessing the immune system in glioblastoma. Br. J. Cancer 119, 1171–1181 (2018).

    PubMed  PubMed Central  Google Scholar 

  32. Meng, Y., Hynynen, K. & Lipsman, N. Applications of focused ultrasound in the brain: from thermoablation to drug delivery. Nat. Rev. Neurol. 17, 7–22 (2021).

    PubMed  Google Scholar 

  33. Bunevicius, A., McDannold, N. J. & Golby, A. J. Focused ultrasound strategies for brain tumor therapy. Oper. Neurosurg. 19, 9–18 (2020).

    Google Scholar 

  34. Elias, W. J. et al. A randomized trial of focused ultrasound thalamotomy for essential tremor. N. Engl. J. Med. 375, 730–739 (2016).

    PubMed  Google Scholar 

  35. Guthkelch, A. N. et al. Treatment of malignant brain tumors with focused ultrasound hyperthermia and radiation: results of a phase I trial. J. Neurooncol. 10, 271–284 (1991).

    CAS  PubMed  Google Scholar 

  36. Castano, A. P., Demidova, T. N. & Hamblin, M. R. Mechanisms in photodynamic therapy: part one–photosensitizers, photochemistry and cellular localization. Photodiagnosis Photodyn. Ther. 1, 279–293 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Castano, A. P., Demidova, T. N. & Hamblin, M. R. Mechanisms in photodynamic therapy: part two–cellular signaling, cell metabolism and modes of cell death. Photodiagnosis Photodyn. Ther. 2, 1–23 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Fingar, V. H. Vascular effects of photodynamic therapy. J. Clin. Laser Med. Surg. 14, 323–328 (1996).

    CAS  PubMed  Google Scholar 

  39. Li, F. et al. Photodynamic therapy boosts anti-glioma immunity in mice: a dependence on the activities of T cells and complement C3. J. Cell. Biochem. 112, 3035–3043 (2011).

    CAS  PubMed  Google Scholar 

  40. Bellnier, D. A. et al. Clinical pharmacokinetics of the PDT photosensitizers porfimer sodium (Photofrin), 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (Photochlor) and 5-ALA-induced protoporphyrin IX. Lasers Surg. Med. 38, 439–444 (2006).

    PubMed  Google Scholar 

  41. Stummer, W. et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 7, 392–401 (2006).

    CAS  PubMed  Google Scholar 

  42. Eljamel, M. S., Goodman, C. & Moseley, H. ALA and Photofrin® fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre phase III randomised controlled trial. Lasers Med. Sci. 23, 361–367 (2008).

    PubMed  Google Scholar 

  43. Schipmann, S. et al. Combination of ALA-induced fluorescence-guided resection and intraoperative open photodynamic therapy for recurrent glioblastoma: case series on a promising dual strategy for local tumor control. J. Neurosurg. 134, 426–436 (2020).

    Google Scholar 

  44. Linde, M. E. Van et al. Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis. J. Neurooncol. 135, 183–192 (2017).

    PubMed  PubMed Central  Google Scholar 

  45. Wang, H.-W. et al. Broadband reflectance measurements of light penetration, blood oxygenation, hemoglobin concentration, and drug concentration in human intraperitoneal tissues before and after photodynamic therapy. J. Biomed. Opt. 10, 014004 (2005).

    Google Scholar 

  46. Akimoto, J. et al. First autopsy analysis of the efficacy of intra-operative additional photodynamic therapy for patients with glioblastoma. Brain Tumor Pathol. 36, 144–151 (2019).

    CAS  PubMed  Google Scholar 

  47. Vermandel, M. et al. Standardized intraoperative 5-ALA photodynamic therapy for newly diagnosed glioblastoma patients: a preliminary analysis of the INDYGO clinical trial. J. Neurooncol. 152, 501–514 (2021).

    CAS  PubMed  Google Scholar 

  48. Jain, R. K. Delivery of novel therapeutic agents in tumors: physiological barriers and strategies. J. Natl Cancer Inst. 81, 570–576 (1989).

    CAS  PubMed  Google Scholar 

  49. Jahangiri, A. et al. Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies. J. Neurosurg. 126, 191–200 (2017).

    PubMed  Google Scholar 

  50. Kunwar, S. et al. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro. Oncol. 12, 871–881 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Jain, R. K. Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev. 9, 253–266 (1990).

    CAS  PubMed  Google Scholar 

  52. Smith, J. H. & Humphrey, J. A. C. Interstitial transport and transvascular fluid exchange during infusion into brain and tumor tissue. Microvasc. Res. 73, 58–73 (2007).

    CAS  PubMed  Google Scholar 

  53. Gimenez, F. et al. Image-guided convection-enhanced delivery of GDNF protein into monkey putamen. Neuroimage 54 (Suppl. 1), 189–195 (2011).

    Google Scholar 

  54. Astary, G. W., Kantorovich, S., Carney, P. R., Mareci, T. H. & Sarntinoranont, M. Regional convection-enhanced delivery of gadolinium-labeled albumin in the rat hippocampus in vivo. J. Neurosci. Methods 187, 129–137 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Sampson, J. H. et al. Colocalization of gadolinium-diethylene triamine pentaacetic acid with high-molecular-weight molecules after intracerebral convection-enhanced delivery in humans. Neurosurgery 69, 668–676 (2011).

    PubMed  Google Scholar 

  56. Saito, R. et al. Regression of recurrent glioblastoma infiltrating the brainstem after convection-enhanced delivery of nimustine hydrochloride: case report. J. Neurosurg. Pediatr. 7, 522–526 (2011).

    PubMed  Google Scholar 

  57. Saito, R. et al. Phase I trial of convection-enhanced delivery of nimustine hydrochloride (ACNU) for brainstem recurrent glioma. Neurooncol. Adv. 2, vdaa033 (2020).

    PubMed  PubMed Central  Google Scholar 

  58. Haar, P. J. et al. Modelling convection-enhanced delivery in normal and oedematous brain. J. Med. Eng. Technol. 38, 76–84 (2014).

    CAS  PubMed  Google Scholar 

  59. White, E. et al. An evaluation of the relationships between catheter design and tissue mechanics in achieving high-flow convection-enhanced delivery. J. Neurosci. Methods 199, 87–97 (2011).

    PubMed  Google Scholar 

  60. Westphal, M. et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro. Oncol. 5, 79–88 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Bregy, A. et al. The role of Gliadel wafers in the treatment of high-grade gliomas. Expert Rev. Anticancer Ther. 13, 1453–1461 (2013).

    CAS  PubMed  Google Scholar 

  62. De Bonis, P. et al. Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. Acta Neurochir. 154, 1371–1378 (2012).

    PubMed  Google Scholar 

  63. Tsai, N. M. et al. The natural compound n-butylidenephthalide derived from Angelica sinensis inhibits malignant brain tumor growth in vitro and in vivo. J. Neurochem. 99, 1251–1262 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Yang, D.-Y. et al. Enhanced antitumor effects of radiotherapy combined local nimustine delivery rendezvousing with oral temozolomide chemotherapy in glioblastoma patients. J. Cancer Res. Ther. 14, 78 (2018).

    PubMed  Google Scholar 

  65. Wilson, C. B. Chemotherapy of brain tumors by continuous arterial infusion. Surgery 55, 640–653 (1964).

    CAS  PubMed  Google Scholar 

  66. D’Amico, R. S. et al. Super selective intra-arterial cerebral infusion of modern chemotherapeutics after blood–brain barrier disruption: where are we now, and where we are going. J. Neurooncol. 147, 261–278 (2020).

    PubMed  Google Scholar 

  67. Karmur, B. S. et al. Blood–brain barrier disruption in neuro-oncology: strategies, failures, and challenges to overcome. Front. Oncol. 10, 563840 (2020).

    PubMed  PubMed Central  Google Scholar 

  68. Boockvar, J. A. et al. Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma: clinical article. J. Neurosurg. 114, 624–632 (2011).

    CAS  PubMed  Google Scholar 

  69. Galla, N. et al. Apparent diffusion coefficient changes predict survival after intra-arterial bevacizumab treatment in recurrent glioblastoma. Neuroradiology 59, 499–505 (2017).

    PubMed  Google Scholar 

  70. Shin, B. J., Burkhardt, J.-K., Riina, H. A. & Boockvar, J. A. Superselective intra-arterial cerebral infusion of novel agents after blood–brain disruption for the treatment of recurrent glioblastoma multiforme: a technical case series. Neurosurg. Clin. 23, 323–329 (2012).

    Google Scholar 

  71. Chakraborty, S. et al. Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study. J. Neurooncol. 128, 405–415 (2016).

    CAS  PubMed  Google Scholar 

  72. Fortin, D., Morin, P. A., Belzile, F., Mathieu, D. & Paré, F. M. Intra-arterial carboplatin as a salvage strategy in the treatment of recurrent glioblastoma multiforme. J. Neurooncol. 119, 397–403 (2014).

    CAS  PubMed  Google Scholar 

  73. Petr, J. et al. Early and late effects of radiochemotherapy on cerebral blood flow in glioblastoma patients measured with non-invasive perfusion MRI. Radiother. Oncol. 118, 24–28 (2016).

    PubMed  Google Scholar 

  74. Svensson, S. F. et al. MR elastography-based tissue stiffness in glioblastomas is associated with reduced cerebral blood flow. Preprint at medRxiv https://doi.org/10.1101/2021.06.11.21258742 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Chow, K. L. et al. Prognostic factors in recurrent glioblastoma multiforme and anaplastic astrocytoma treated with selective intra-arterial chemotherapy. Am. J. Neuroradiol. 21, 471–478 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Joshi, S. et al. Transient cerebral hypoperfusion assisted intraarterial cationic liposome delivery to brain tissue. J. Neurooncol. 118, 73–82 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Riina, H. A. et al. Balloon-assisted superselective intra-arterial cerebral infusion of bevacizumab for malignant brainstem glioma: a technical note. Interv. Neuroradiol. 16, 71–76 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Jackson, C. M., Choi, J. & Lim, M. Mechanisms of immunotherapy resistance: lessons from glioblastoma. Nat. Immunol. 20, 1100–1109 (2019).

    CAS  PubMed  Google Scholar 

  79. McGranahan, T., Therkelsen, K. E., Ahmad, S. & Nagpal, S. Current state of immunotherapy for treatment of glioblastoma. Curr. Treat. Options Oncol. 20, 24 (2019).

    PubMed  PubMed Central  Google Scholar 

  80. Weller, M. & Le Rhun, E. Immunotherapy for glioblastoma: quo vadis? Nat. Rev. Clin. Oncol. 16, 405–406 (2019).

    CAS  PubMed  Google Scholar 

  81. Chiocca, E. A., Nassiri, F., Wang, J., Peruzzi, P. & Zadeh, G. Viral and other therapies for recurrent glioblastoma: is a 24-month durable response unusual? Neuro. Oncol. 21, 14–25 (2019).

    CAS  PubMed  Google Scholar 

  82. Auffinger, B., Ahmed, A. U. & Lesniak, M. S. Oncolytic virotherapy for malignant glioma: translating laboratory insights into clinical practice. Front. Oncol. 3, 32 (2013).

    PubMed  PubMed Central  Google Scholar 

  83. Martikainen, M. & Essand, M. Virus-based immunotherapy of glioblastoma. Cancers 11, 186 (2019).

    CAS  PubMed Central  Google Scholar 

  84. Harsh, G. R. et al. Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study. J. Neurosurg. 92, 804–811 (2000).

    CAS  PubMed  Google Scholar 

  85. Rainov, N. G. et al. Temozolomide enhances herpes simplex virus thymidine kinase/ganciclovir therapy of malignant glioma. Cancer Gene Ther. 8, 662–668 (2001).

    CAS  PubMed  Google Scholar 

  86. Nestler, U. et al. The combination of adenoviral HSV TK gene therapy and radiation is effective in athymic mouse glioblastoma xenografts without increasing toxic side effects. J. Neurooncol. 67, 177–188 (2004).

    PubMed  Google Scholar 

  87. Wheeler, L. A. et al. Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. Neuro. Oncol. 18, 1137–1145 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ji, N. et al. Adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of recurrent high-grade glioma. Oncotarget 7, 4369–4378 (2016).

    PubMed  Google Scholar 

  89. Chiocca, E. A. et al. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: results of a phase 1 trial. Sci. Transl Med. 11, eaaw5680 (2019).

    PubMed  PubMed Central  Google Scholar 

  90. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3, 133–146 (2003).

    CAS  PubMed  Google Scholar 

  91. Zhang, L. et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin. Cancer Res. 21, 2278–2288 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Car, B. D., Eng, V. M., Lipman, J. M. & Anderson, T. D. The toxicology of interleukin-12: a review. Toxicol. Pathol. 27, 58–63 (1999).

    CAS  PubMed  Google Scholar 

  93. Cai, H. et al. Plasma pharmacokinetics of veledimex, a small-molecule activator ligand for a proprietary gene therapy promoter system, in healthy subjects. Clin. Pharmacol. Drug Dev. 6, 246–257 (2017).

    CAS  PubMed  Google Scholar 

  94. Ostertag, D. et al. Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Neuro Oncol. 14, 145–159 (2012).

    CAS  PubMed  Google Scholar 

  95. Cloughesy, T. F. et al. Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma. Sci. Transl Med. 8, 341ra75 (2016).

    PubMed  PubMed Central  Google Scholar 

  96. Desjardins, A. et al. Recurrent glioblastoma treated with recombinant poliovirus. N. Engl. J. Med. 379, 150–161 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Brown, M. C. et al. Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs. Sci. Transl Med. 9, eaan4220 (2017).

    PubMed  PubMed Central  Google Scholar 

  98. Lang, F. F. et al. Phase I study of DNX-2401 (delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J. Clin. Oncol. 36, 1419–1427 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Maher, E. A. et al. Malignant glioma: genetics and biology of a grave matter. Genes Dev. 15, 1311–1333 (2001).

    CAS  PubMed  Google Scholar 

  100. Fueyo, J. et al. Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. J. Natl Cancer Inst. 95, 652–660 (2003).

    CAS  PubMed  Google Scholar 

  101. Mineta, T., Rabkin, S. D., Yazaki, T., Hunter, W. D. & Martuza, R. L. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat. Med. 1, 938–943 (1995).

    CAS  PubMed  Google Scholar 

  102. Markert, J. M. et al. A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol. Ther. 22, 1048–1055 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Friedman, G. K. et al. Enhanced sensitivity of patient-derived pediatric high-grade brain tumor xenografts to oncolytic HSV-1 virotherapy correlates with nectin-1 expression. Sci. Rep. 8, 13930 (2018).

    PubMed  PubMed Central  Google Scholar 

  104. Friedman, G. K. et al. Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas. N. Engl. J. Med. 384, 1613–1622 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Liu, E. K., Yu, S., Sulman, E. P. & Kurz, S. C. Racial and socioeconomic disparities differentially affect overall and cause-specific survival in glioblastoma. J. Neurooncol. 149, 55–64 (2020).

    PubMed  Google Scholar 

  106. Rainov, N. G. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum. Gene Ther. 11, 2389–2401 (2000).

    CAS  PubMed  Google Scholar 

  107. Kawakami, M., Kawakami, K. & Puri, R. K. Intratumor administration of interleukin 13 receptor-targeted cytotoxin induces apoptotic cell death in human malignant glioma tumor xenografts. Mol. Cancer Ther. 1, 999–1007 (2002).

    CAS  PubMed  Google Scholar 

  108. Krieg, A. M. Antitumor applications of stimulating Toll-like receptor 9 with CpG oligodeoxynucleotides. Curr. Oncol. Rep. 6, 88–95 (2004).

    PubMed  Google Scholar 

  109. Meng, Y. et al. Expression of TLR9 within human glioblastoma. J. Neurooncol. 88, 19–25 (2008).

    PubMed  Google Scholar 

  110. Andaloussi, S. E. L., Mäger, I., Breakefield, X. O. & Wood, M. J. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 12, 347–357 (2013).

    Google Scholar 

  111. Carpentier, A. et al. Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro. Oncol. 12, 401–408 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Ursu, R. et al. Intracerebral injection of CpG oligonucleotide for patients with de novo glioblastoma–a phase II multicentric, randomised study. Eur. J. Cancer 73, 30–37 (2017).

    CAS  PubMed  Google Scholar 

  113. Nduom, E. K., Weller, M. & Heimberger, A. B. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 17 (Suppl. 7), vii9–vii14 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Mann, J., Ramakrishna, R., Magge, R. & Wernicke, A. G. Advances in radiotherapy for glioblastoma. Front. Neurol. 8, 748 (2018).

    PubMed  PubMed Central  Google Scholar 

  115. Barbarite, E. et al. The role of brachytherapy in the treatment of glioblastoma multiforme. Neurosurg. Rev. 40, 195–211 (2017).

    PubMed  Google Scholar 

  116. Bartek, J. et al. Receipt of brachytherapy is an independent predictor of survival in glioblastoma in the Surveillance, Epidemiology, and End Results database. J. Neurooncol. 145, 75–83 (2019).

    CAS  PubMed  Google Scholar 

  117. Field, K. M. et al. Clinical trial participation and outcome for patients with glioblastoma: multivariate analysis from a comprehensive dataset. J. Clin. Neurosci. 20, 783–789 (2013).

    PubMed  Google Scholar 

  118. Skaga, E. et al. Real-world validity of randomized controlled phase III trials in newly diagnosed glioblastoma: to whom do the results of the trials apply? Neurooncol. Adv. 3, vdab008 (2021).

    PubMed  PubMed Central  Google Scholar 

  119. Schwartz, C. et al. Outcome and toxicity profile of salvage low-dose-rate iodine-125 stereotactic brachytherapy in recurrent high-grade gliomas. Acta Neurochir. 157, 1757–1764 (2015).

    PubMed  Google Scholar 

  120. Kickingereder, P. et al. Low-dose rate stereotactic iodine-125 brachytherapy for the treatment of inoperable primary and recurrent glioblastoma: single-center experience with 201 cases. J. Neurooncol. 120, 615–623 (2014).

    CAS  PubMed  Google Scholar 

  121. Phillips, W. T. et al. Rhenium-186 liposomes as convection-enhanced nanoparticle brachytherapy for treatment of glioblastoma. Neuro. Oncol. 14, 416–425 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Pilar, A., Gupta, M., Ghosh Laskar, S. & Laskar, S. Intraoperative radiotherapy: review of techniques and results. Ecancermedicalscience 11, 750 (2017).

    PubMed  PubMed Central  Google Scholar 

  123. Sarria, G. R. et al. Intraoperative radiotherapy for glioblastoma: an international pooled analysis. Radiother. Oncol. 142, 162–167 (2020).

    PubMed  Google Scholar 

  124. Aboody, K. S. et al. Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies. Sci. Transl Med. 5, 184ra59 (2013).

    PubMed  Google Scholar 

  125. Pacioni, S. et al. Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts. Stem Cell Res. Ther. 8, 53 (2017).

    PubMed  PubMed Central  Google Scholar 

  126. Portnow, J. et al. Neural stem cell-based anticancer gene therapy: a first-in-human study in recurrent high-grade glioma patients. Clin. Cancer Res. 23, 2951–2960 (2017).

    CAS  PubMed  Google Scholar 

  127. Kim, S. U. Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology 24, 159–171 (2004).

    PubMed  Google Scholar 

  128. Fares, J. et al. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial. Lancet Oncol. 22, 1103–1114 (2021).

    CAS  PubMed  Google Scholar 

  129. Ahmed, A. U. et al. A preclinical evaluation of neural stem cell-based cell carrier for targeted antiglioma oncolytic virotherapy. J. Natl Cancer Inst. 105, 968–977 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Salinas, R. D., Durgin, J. S. & O’Rourke, D. M. Potential of glioblastoma-targeted chimeric antigen receptor (CAR) T-cell therapy. CNS Drugs 34, 127–145 (2020).

    CAS  PubMed  Google Scholar 

  131. Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Spaeth, E., Klopp, A., Dembinski, J., Andreeff, M. & Marini, F. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther. 15, 730–738 (2008).

    CAS  PubMed  Google Scholar 

  133. Choi, S. H. et al. Tumor resection recruits effector T cells and boosts therapeutic efficacy of encapsulated stem cells expressing IFNβ in glioblastomas. Clin. Cancer Res. 23, 7047–7058 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Alayo, Q. A. et al. Glioblastoma infiltration of both tumor- and virus-antigen specific cytotoxic T cells correlates with experimental virotherapy responses. Sci. Rep. 10, 5095 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Neftel, C. et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 178, 835–849.e21 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Felsberg, J. et al. Epidermal growth factor receptor variant III (EGFRvIII) positivity in EGFR-amplified glioblastomas: prognostic role and comparison between primary and recurrent tumors. Clin. Cancer Res. 23, 6846–6855 (2017).

    CAS  PubMed  Google Scholar 

  137. Chongsathidkiet, P. et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat. Med. 24, 1459–1468 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Cloughesy, T. F. et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat. Med. 25, 477–486 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Chen, A. M. et al. Phase I trial of gross total resection, permanent iodine-125 brachytherapy, and hyperfractionated radiotherapy for newly diagnosed glioblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 69, 825–830 (2007).

    CAS  PubMed  Google Scholar 

  140. Cabrera, A. R. et al. Radiation therapy for glioblastoma: executive summary of an American Society for Radiation Oncology evidence-based clinical practice guideline. Pract. Radiat. Oncol. 6, 217–225 (2016).

    PubMed  Google Scholar 

  141. Puente, Pdela et al. Injectable hydrogels for localized chemotherapy and radiotherapy in brain tumors. J. Pharm. Sci. 107, 922–933 (2018).

    CAS  PubMed  Google Scholar 

  142. Chen, P. Y. et al. Comparing routes of delivery for nanoliposomal irinotecan shows superior anti-tumor activity of local administration in treating intracranial glioblastoma xenografts. Neuro Oncol. 15, 189–197 (2013).

    CAS  PubMed  Google Scholar 

  143. Floyd, J. A., Galperin, A. & Ratner, B. D. Drug encapsulated polymeric microspheres for intracranial tumor therapy: a review of the literature. Adv. Drug Deliv. Rev. 91, 23–37 (2015).

    CAS  PubMed  Google Scholar 

  144. Hernán Pérez de la Ossa, D. et al. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme. PLoS ONE 8, 2–9 (2013).

    Google Scholar 

  145. Mehta, N. et al. Bacterial carriers for glioblastoma therapy. Mol. Ther. Oncolytics 4, 1–17 (2017).

    CAS  PubMed  Google Scholar 

  146. Cohen, Z. R. et al. Localized RNAi therapeutics of chemoresistant grade IV glioma using hyaluronan-grafted lipid-based nanoparticles. ACS Nano 9, 1581–1591 (2015).

    CAS  PubMed  Google Scholar 

  147. Sharabi, S. et al. The application of point source electroporation and chemotherapy for the treatment of glioma: a randomized controlled rat study. Sci. Rep. 10, 2178 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Giuliano, A. R. et al. Participation of minorities in cancer research: the influence of structural, cultural, and linguistic factors. Ann. Epidemiol. 10, S22–S34 (2000).

    CAS  PubMed  Google Scholar 

  149. Pitter, K. L. et al. Corticosteroids compromise survival in glioblastoma. Brain 139, 1458–1471 (2016).

    PubMed  PubMed Central  Google Scholar 

  150. Gorlia, T. et al. New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: a pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials. Eur. J. Cancer 48, 1176–1184 (2012).

    PubMed  Google Scholar 

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Acknowledgements

The authors thank M. E. Haeflich for proofreading this manuscript for typographical and grammatical errors; skilled editorial assistance from S. McDavitt; and insights from X. Breakefield. M.L.D.B. is supported by grant NIH NCI R35 CA232103. T.S.v.S. is supported by grants from the Bontius Stichting, the Nijbakker-Morra Fund, Foundation Vrijvrouwe van Renswoude and the Bekker-la Bastide Fund. T.S.v.S. and E.A.C. are supported by NIH grant P01 CA069246.

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T.S.v.S. researched data for the article. All authors contributed substantially to discussion of the content. T.S.v.S and M.L.D.B. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Thomas S. van Solinge.

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Competing interests

E.A.C. is currently an advisor to Advantagene, Alcyone Biosciences, Insightec, DNAtrix, Immunomic Therapeutics, Seneca Therapeutics, GlaxoSmithKline and Voyager Therapeutics and has equity interest in DNAtrix, Immunomic Therapeutics and Seneca Therapeutics; he has also advised Oncorus, Merck, Tocagen, Ziopharm, Stemgen, NanoTx., Ziopharm Oncology, Cerebral Therapeutics, Genenta. Merck, Janssen, Karcinolysis, Shanghai Biotech and Sangamo Therapeutics. He has received research support from the NIH, the US Department of Defense, the American Brain Tumor Association, the National Brain Tumor Society, the Alliance for Cancer Gene Therapy, the Neurosurgical Research Education Foundation, Advantagene, NewLink Genetics and Amgen. He is also a named inventor on patents related to oncolytic HSV-1 and non-coding RNAs. The other authors declare no competing interests.

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Review criteria

In December 2020, we searched PubMed and Embase for studies utilizing any form of local therapy in glioblastoma. Keywords, Mesh terms and Emtree terms including “glioblastoma”, “glioma”, “local therapy”, “localized therapy”, “convection enhanced delivery”, “thermotherapy”, “wafer”, “brachytherapy”, “photodynamic therapy” and their synonyms were combined to form our search. Titles and abstracts were screened for relevant articles and studies. References from full-text articles were screened for additional studies. Articles had to be written in English and published within the past 20 years. Studies performed before implementation of the Stupp protocol were excluded, unless deemed relevant to current studies or patient care. Case reports were also excluded. Additional papers were recommended by all authors. For current clinical trials, ClinicalTrials.gov was searched for disease “glioblastoma” and “glioma”, and all trials with status ‘not yet recruiting’, ‘recruiting’, ‘enrolling by invitation’, ‘active, not recruiting’, or ‘available’.

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van Solinge, T.S., Nieland, L., Chiocca, E.A. et al. Advances in local therapy for glioblastoma — taking the fight to the tumour. Nat Rev Neurol 18, 221–236 (2022). https://doi.org/10.1038/s41582-022-00621-0

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