L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 May 2024
28 May 2024
Historique:
received:
29
09
2023
accepted:
30
04
2024
medline:
29
5
2024
pubmed:
29
5
2024
entrez:
28
5
2024
Statut:
epublish
Résumé
The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12
Identifiants
pubmed: 38806504
doi: 10.1038/s41467-024-48416-9
pii: 10.1038/s41467-024-48416-9
doi:
Substances chimiques
Aptamers, Nucleotide
0
Chemokine CXCL12
0
CXCL12 protein, human
0
Types de publication
Journal Article
Clinical Trial, Phase II
Clinical Trial, Phase I
Langues
eng
Sous-ensembles de citation
IM
Pagination
4210Informations de copyright
© 2024. The Author(s).
Références
Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro-Oncol. 21, v1–v100 (2019).
pubmed: 31675094
pmcid: 6823730
doi: 10.1093/neuonc/noz150
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).
pubmed: 19269895
doi: 10.1016/S1470-2045(09)70025-7
Wen, P. Y. et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro-Oncol. 22, 1073–1113 (2020).
pubmed: 32328653
pmcid: 7594557
doi: 10.1093/neuonc/noaa106
Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).
pubmed: 15758010
doi: 10.1056/NEJMoa043331
Kreth, F.-W. et al. Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy. Ann. Oncol. 24, 3117–3123 (2013).
pubmed: 24130262
doi: 10.1093/annonc/mdt388
Nabors, L. B. et al. Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Neuro-Oncol. 17, 708–717 (2015).
pubmed: 25762461
pmcid: 4482861
doi: 10.1093/neuonc/nou356
Stupp, R. et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318, 2306–2316 (2017).
pubmed: 29260225
pmcid: 5820703
doi: 10.1001/jama.2017.18718
Sim, H.-W. et al. A randomized phase II trial of veliparib, radiotherapy, and temozolomide in patients with unmethylated MGMT glioblastoma: the VERTU study. Neuro Oncol. 23, 1736–1749 (2021).
pubmed: 33984151
pmcid: 8485443
doi: 10.1093/neuonc/noab111
Stummer, W. et al. Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62, 564–576 (2008).
pubmed: 18425006
doi: 10.1227/01.neu.0000317304.31579.17
Aldave, G. et al. Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic acid-guided surgery. Neurosurgery 72, 915–921 (2013).
pubmed: 23685503
doi: 10.1227/NEU.0b013e31828c3974
Karschnia, P. et al. Prognostic validation of a new classification system for extent of resection in glioblastoma: A report of the RANO resect group. Neuro-Oncol. 25, 940–954 (2023).
pubmed: 35961053
doi: 10.1093/neuonc/noac193
Brown, T. J. et al. Association of the extent of resection with survival in glioblastoma: a systematic review and meta-analysis. JAMA Oncol. 2, 1460 (2016).
pubmed: 27310651
pmcid: 6438173
doi: 10.1001/jamaoncol.2016.1373
Brown, J. M. Vasculogenesis: a crucial player in the resistance of solid tumours to radiotherapy. Br. J. Radiol. 87, 20130686 (2014).
pubmed: 24338942
pmcid: 4064599
doi: 10.1259/bjr.20130686
Gerhardt, H. et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J. Cell Biol. 161, 1163–1177 (2003).
pubmed: 12810700
pmcid: 2172999
doi: 10.1083/jcb.200302047
Tammela, T. et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656–660 (2008).
pubmed: 18594512
doi: 10.1038/nature07083
Takahashi, T. et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat. Med. 5, 434–438 (1999).
pubmed: 10202935
doi: 10.1038/7434
Ceradini, D. J. et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat. Med. 10, 858–864 (2004).
pubmed: 15235597
doi: 10.1038/nm1075
Du, R. et al. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008).
pubmed: 18328425
pmcid: 2643426
doi: 10.1016/j.ccr.2008.01.034
Walters, M. J. et al. Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats. Br. J. Cancer 110, 1179–1188 (2014).
pubmed: 24423923
pmcid: 3950859
doi: 10.1038/bjc.2013.830
Giordano, F. A. et al. Targeting the post-irradiation tumor microenvironment in glioblastoma via inhibition of CXCL12. Cancers (Basel) 11, 272 (2019).
pubmed: 30813533
doi: 10.3390/cancers11030272
Brown, J. M. Radiation damage to tumor vasculature initiates a program that promotes tumor recurrences. Int. J. Radiat. Oncol. 108, 734–744 (2020).
doi: 10.1016/j.ijrobp.2020.05.028
Rempel, S. A., Dudas, S., Ge, S. & Gutiérrez, J. A. Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin. Cancer Res. 6, 102–111 (2000).
pubmed: 10656438
Tabatabai, G., Frank, B., Möhle, R., Weller, M. & Wick, W. Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-beta-dependent HIF-1alpha-mediated induction of CXCL12. Brain 129, 2426–2435 (2006).
pubmed: 16835250
doi: 10.1093/brain/awl173
Komatani, H., Sugita, Y., Arakawa, F., Ohshima, K. & Shigemori, M. Expression of CXCL12 on pseudopalisading cells and proliferating microvessels in glioblastomas: an accelerated growth factor in glioblastomas. Int. J. Oncol. 34, 665–672 (2009).
pubmed: 19212671
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).
pubmed: 24277834
pmcid: 3864274
doi: 10.1073/pnas.1320318110
Fearon, D. T. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol. Res. 2, 187–193 (2014).
pubmed: 24778314
doi: 10.1158/2326-6066.CIR-14-0002
Seo, Y. D. et al. Mobilization of CD8+ T cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer. Clin. Cancer Res. 25, 3934–3945 (2019).
pubmed: 30940657
pmcid: 6606359
doi: 10.1158/1078-0432.CCR-19-0081
Maderna, E., Salmaggi, A., Calatozzolo, C., Limido, L. & Pollo, B. Nestin, PDGFRbeta, CXCL12 and VEGF in glioma patients: different profiles of (pro-angiogenic) molecule expression are related with tumor grade and may provide prognostic information. Cancer Biol. Ther. 6, 1018–1024 (2007).
pubmed: 17611402
doi: 10.4161/cbt.6.7.4362
Hattermann, K. et al. The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res. 70, 3299–3308 (2010).
pubmed: 20388803
doi: 10.1158/0008-5472.CAN-09-3642
Kioi, M. et al. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120, 694–705 (2010).
pubmed: 20179352
pmcid: 2827954
doi: 10.1172/JCI40283
Thomas, R. P. et al. Macrophage exclusion after radiation therapy (MERT): a first in human phase I/II trial using a CXCR4 Inhibitor in glioblastoma. Clin. Cancer Res. 25, 6948–6957 (2019).
pubmed: 31537527
pmcid: 6891194
doi: 10.1158/1078-0432.CCR-19-1421
Liu, S.-C. et al. Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats. Neuro-Oncol. 16, 21–28 (2014).
pubmed: 24335554
doi: 10.1093/neuonc/not149
Wlotzka, B. et al. In vivo properties of an anti-GnRH Spiegelmer: an example of an oligonucleotide-based therapeutic substance class. Proc. Natl Acad. Sci. USA 99, 8898–8902 (2002).
pubmed: 12070349
pmcid: 124395
doi: 10.1073/pnas.132067399
Vater, A. et al. Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12. Clin. Pharm. Ther. 94, 150–157 (2013).
doi: 10.1038/clpt.2013.58
Abdelfattah, N. et al. Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target. Nat. Commun. 13, 767 (2022).
pubmed: 35140215
pmcid: 8828877
doi: 10.1038/s41467-022-28372-y
Black, S. et al. CODEX multiplexed tissue imaging with DNA-conjugated antibodies. Nat. Protoc. 16, 3802–3835 (2021).
pubmed: 34215862
pmcid: 8647621
doi: 10.1038/s41596-021-00556-8
Shekarian, T. et al. Immunotherapy of glioblastoma explants induces interferon-γ responses and spatial immune cell rearrangements in tumor center, but not periphery. Sci. Adv. 8, eabn9440 (2022).
pubmed: 35776791
pmcid: 10883360
doi: 10.1126/sciadv.abn9440
Greenfield, J. P., Cobb, W. S. & Lyden, D. Resisting arrest: a switch from angiogenesis to vasculogenesis in recurrent malignant gliomas. J. Clin. Invest 120, 663–667 (2010).
pubmed: 20179347
pmcid: 2827970
doi: 10.1172/JCI42345
Kozin, S. V. et al. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res 70, 5679–5685 (2010).
pubmed: 20631066
pmcid: 2918387
doi: 10.1158/0008-5472.CAN-09-4446
Tabouret, E. et al. Recurrence of glioblastoma after radio-chemotherapy is associated with an angiogenic switch to the CXCL12-CXCR4 pathway. Oncotarget 6, 11664–11675 (2015).
pubmed: 25860928
pmcid: 4484484
doi: 10.18632/oncotarget.3256
Yeo, A. T. et al. Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression. Nat. Immunol. 23, 971–984 (2022).
pubmed: 35624211
pmcid: 9174057
doi: 10.1038/s41590-022-01215-0
Hoogstrate, Y. et al. Transcriptome analysis reveals tumor microenvironment changes in glioblastoma. Cancer Cell 41, 678–692.e7 (2023).
pubmed: 36898379
doi: 10.1016/j.ccell.2023.02.019
Karimi, E. et al. Single-cell spatial immune landscapes of primary and metastatic brain tumours. Nature 614, 555–563 (2023).
pubmed: 36725935
pmcid: 9931580
doi: 10.1038/s41586-022-05680-3
Polley, M.-Y. C. & Dignam, J. J. Statistical considerations in the evaluation of continuous biomarkers. J. Nucl. Med. 62, 605–611 (2021).
pubmed: 33579807
pmcid: 8844257
doi: 10.2967/jnumed.120.251520
Tsien, C. I. et al. NRG Oncology/RTOG1205: a randomized phase II trial of concurrent bevacizumab and reirradiation versus bevacizumab alone as treatment for recurrent glioblastoma. J. Clin. Oncol. 41, 1285–1295 (2023).
pubmed: 36260832
doi: 10.1200/JCO.22.00164
Lombardi, G. et al. Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 20, 110–119 (2019).
pubmed: 30522967
doi: 10.1016/S1470-2045(18)30675-2
Wu, D. et al. The blood–brain barrier: structure, regulation, and drug delivery. Sig Transduct. Target Ther. 8, 217 (2023).
doi: 10.1038/s41392-023-01481-w
Hoellenriegel, J. et al. The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization. Blood 123, 1032–1039 (2014).
pubmed: 24277076
pmcid: 4123413
doi: 10.1182/blood-2013-03-493924
Chernikova, S., Ahn, G.-O., Liu, S.-C., Stafford, J. & Brown, J. M. Abstract C291: targeting SDF-1 (CXCL12) pathway to inhibit the recurrence of breast cancer brain metastases after whole-brain irradiation. Mol. Cancer Ther. 12, C291–C291 (2013).
doi: 10.1158/1535-7163.TARG-13-C291
Deng, L. et al. SDF-1 blockade enhances anti-VEGF therapy of glioblastoma and can be monitored by MRI. Neoplasia 19, 1–7 (2017).
pubmed: 27940247
doi: 10.1016/j.neo.2016.11.010
Le Tourneau, C., Lee, J. J. & Siu, L. L. Dose escalation methods in phase I cancer clinical trials. J. Natl. Cancer Inst. 101, 708–720 (2009).
pubmed: 19436029
pmcid: 2684552
doi: 10.1093/jnci/djp079
Niyazi, M. et al. ESTRO-ACROP guideline ‘target delineation of glioblastomas. Radiother. Oncol. 118, 35–42 (2016).
pubmed: 26777122
doi: 10.1016/j.radonc.2015.12.003
Ellingson, B. M., Wen, P. Y. & Cloughesy, T. F. Modified criteria for radiographic response assessment in glioblastoma clinical trials. Neurotherapeutics 14, 307–320 (2017).
pubmed: 28108885
pmcid: 5398984
doi: 10.1007/s13311-016-0507-6
Mikeska, T. et al. Optimization of quantitative MGMT promoter methylation analysis using pyrosequencing and combined bisulfite restriction analysis. J. Mol. Diagn. 9, 368–381 (2007).
pubmed: 17591937
pmcid: 1899414
doi: 10.2353/jmoldx.2007.060167
Krämer, B. et al. Single-cell RNA sequencing identifies a population of human liver-type ILC1s. Cell Rep. 42, 111937 (2023).
pubmed: 36640314
pmcid: 9950534
doi: 10.1016/j.celrep.2022.111937
Marsh, S., Salmon, M. & Hoffman, P. samuel-marsh/scCustomize: Version 1.1.1. https://doi.org/10.5281/ZENODO.5706430 . (2023).