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L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy and bevacizumab in newly-diagnosed glioblastoma: expansion of the phase I/II GLORIA trial

Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). We performed spatial expression analyses, providing a rationale for dual inhibition of two non-redundant, spatially distinct acting factors, CXCL12 and VEGF. Subsequently, we expanded a multicen...

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Main Authors: Giordano, Frank Anton (Author) , Layer, Julian P. (Author) , Turiello, Roberta (Author) , Friker, Lea L. (Author) , Mirallas, Oriol (Author) , Pregler, Barbara E. F. (Author) , Potthoff, Anna-Laura (Author) , Zeyen, Thomas (Author) , Weller, Johannes (Author) , Sperk, Elena (Author) , Sahm, Katharina (Author) , Oster, Christoph (Author) , Kebir, Sied (Author) , Hambsch, Peter (Author) , Schäfer, Niklas (Author) , Kadzik, Sebastian (Author) , Renovanz, Mirjam (Author) , Pietsch, Torsten (Author) , Bisdas, Sotirios (Author) , Sepúlveda-Sánchez, Juan Manuel (Author) , Gómez-Puerto, Diego (Author) , Vieito, Maria (Author) , Platten, Michael (Author) , Gkika, Eleni (Author) , Grauer, Oliver M. (Author) , Tabatabai, Ghazaleh (Author) , Schneider, Matthias (Author) , Glas, Martin (Author) , Seidel, Clemens (Author) , Herrlinger, Ulrich (Author) , Hölzel, Michael (Author)
Format: Article (Journal)
Language:English
Published: 08 April 2026
In: Nature Communications
Year: 2026, Volume: 17, Pages: 1-17
ISSN:2041-1723
DOI:10.1038/s41467-026-71362-7
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-026-71362-7
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-026-71362-7
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Author Notes:Frank A. Giordano, Julian P. Layer, Roberta Turiello, Lea L. Friker, Oriol Mirallas, Barbara E.F. Pregler, Anna-Laura Potthoff, Thomas Zeyen, Johannes Weller, Elena Sperk, Katharina Sahm, Christoph Oster, Sied Kebir, Peter Hambsch, Niklas Schäfer, Sebastian Kadzik, Mirjam Renovanz, Torsten Pietsch, Sotirios Bisdas, Juan Manuel Sepúlveda-Sánchez, Diego Gómez-Puerto, Maria Vieito, Michael Platten, Eleni Gkika, Oliver M. Grauer, Ghazaleh Tabatabai, Matthias Schneider, Martin Glas, Clemens Seidel, Ulrich Herrlinger & Michael Hölzel
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Summary:Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). We performed spatial expression analyses, providing a rationale for dual inhibition of two non-redundant, spatially distinct acting factors, CXCL12 and VEGF. Subsequently, we expanded a multicentric phase 1/2 trial (NCT04121455), which initially combined RT and the CXCL12-neutralizing L-RNA-aptamer olaptesed pegol (NOX-A12) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT promoter methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose, recommended phase 2 dose, NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life, median progression-free survival (PFS), 6-months PFS and overall survival (OS). For the expansion arm, six patients were included that additionally received the VEGF-targeting antibody bevacizumab (BEV) to RT and NOX-A12. Combinatory treatment was well-tolerated and safe with no treatment-related deaths, resulting in abrogated tumor perfusion (rCBV, FTBhigh) and delayed tumor regrowth as per mRANO. Median progression-free (PFS) and overall survival (OS) after RT + BEV + NOX-A12 were 9.1 and 19.9 months, respectively, significantly outperforming RT + NOX-A12 (p = 0.009; p = 0.021) in a post-hoc comparative analysis, with two patients exceeding 2-year OS. These findings establish proof-of-principle for dual inhibition of CXCL12 and VEGF in patients with newly-diagnosed GBM following RT.
Item Description:Gesehen am 30.04.2026
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-026-71362-7

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