2. Academic Validation
  3. Tailoring glioblastoma treatment based on longitudinal analysis of post-surgical tumor microenvironment

Tailoring glioblastoma treatment based on longitudinal analysis of post-surgical tumor microenvironment

  • J Exp Clin Cancer Res. 2024 Nov 28;43(1):311. doi: 10.1186/s13046-024-03231-4.
Chiara Bastiancich 1 2 3 4,  Emmanuel Snacel-Fazy 5,  Samantha Fernandez 6,  Stéphane Robert 7,  Roberta Stacchini 5,  Léa Plantureux 7,  Sébastien Boissonneau 8 9,  Benoit Testud 10 11 12,  Benjamin Guillet 6 7 13,  Franck Debarbieux 6 14 15,  Hervé Luche 16,  Dominique Figarella-Branger 5,  Marie-Anne Estève 5 17,  Emeline Tabouret 5 18 19,  Aurélie Tchoghandjian 20 21
Affiliations

Affiliations

  • 1 Aix-Marseille Univ, CNRS, INP, Institute of Neurophysiopathology UMR7051, Team Gliomagenesis and Microenvironment, Faculté des Sciences Médicales et Paramédicales - Secteur Timone, 27, Bd Jean Moulin, Marseille, 13005, France. chiara.bastiancich@univ-amu.fr.
  • 2 Department of Drug Science and Technology, University of Turin, Turin, 10125, Italy. chiara.bastiancich@univ-amu.fr.
  • 3 UCLouvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Avenue Mounier 73, Brussels, 1200, Belgium. chiara.bastiancich@univ-amu.fr.
  • 4 Aix-Marseille Univ, Réseau Préclinique Et Translationnel de Recherche en Neuro-Oncologie, Plateforme PETRA"TECH", Marseille, 13005, France. chiara.bastiancich@univ-amu.fr.
  • 5 Aix-Marseille Univ, CNRS, INP, Institute of Neurophysiopathology UMR7051, Team Gliomagenesis and Microenvironment, Faculté des Sciences Médicales et Paramédicales - Secteur Timone, 27, Bd Jean Moulin, Marseille, 13005, France.
  • 6 Aix Marseille Univ, CNRS, CERIMED, Marseille, France.
  • 7 Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France.
  • 8 Department of Neuro-Surgery, AP-HM, Hôpital Universitaire Timone, Marseille, 13005, France.
  • 9 Department of Neuro-Surgery, Valenciennes Hospital, Valenciennes, 59300, France.
  • 10 Aix Marseille Univ, CNRS, CRMBM, Marseille, France.
  • 11 Aix Marseille Univ, APHM, Hôpital Universitaire Timone, CEMEREM, Marseille, 13005, France.
  • 12 Department of Neuroradiology, Aix Marseille Univ, APHM, Hôpital Universitaire Timone, Marseille, 13005, France.
  • 13 Aix Marseille Univ, APHM, Hôpital Timone, Pôle Pharmacie, Radiopharmacie, Marseille, 13005, France.
  • 14 Aix Marseille Univ, CNRS, INT, Inst Neurosci Timone, Marseille, France.
  • 15 Institut Universitaire de France, Paris, 75005, France.
  • 16 Aix-Marseille Univ, CNRS, INSERM, CIPHE, Marseille, 13009, France.
  • 17 Aix Marseille Univ, APHM, Hôpital Timone, Service Pharmacie, Marseille, 13005, France.
  • 18 AP-HM, CHU Timone, Service de Neurooncologie, Marseille, France.
  • 19 Aix-Marseille Univ, Réseau Préclinique Et Translationnel de Recherche en Neuro-Oncologie, Plateforme PE"TRANSLA", Marseille, 13005, France.
  • 20 Aix-Marseille Univ, CNRS, INP, Institute of Neurophysiopathology UMR7051, Team Gliomagenesis and Microenvironment, Faculté des Sciences Médicales et Paramédicales - Secteur Timone, 27, Bd Jean Moulin, Marseille, 13005, France. aurelie.tchoghandjian@univ-amu.fr.
  • 21 Aix-Marseille Univ, Réseau Préclinique Et Translationnel de Recherche en Neuro-Oncologie, Plateforme PETRA"TECH", Marseille, 13005, France. aurelie.tchoghandjian@univ-amu.fr.
PMID: 39605004 DOI: 10.1186/s13046-024-03231-4
Abstract

Glioblastoma (GBM), an incurable primary brain tumor, typically requires surgical intervention followed by chemoradiation; however, recurrences remain fatal. Our previous work demonstrated that a nanomedicine hydrogel (GemC12-LNC) delays recurrence when administered post-surgery. However, tumor debulking also triggers time-dependent immune reactions that promote recurrence at the resection cavity borders. We hypothesized that combining the hydrogel with an immunomodulatory drug could enhance therapeutic outcomes. A thorough characterization of the post-surgical microenvironment (SMe) is crucial to guide combinatorial approaches.In this study, we performed cellular resolution imaging, flow cytometry and spatial hyperplexed immunofluorescence imaging to characterize the SMe in a syngeneic mouse model of tumor resection. Owing to our dynamic approach, we observed transient opening of the blood-brain barrier (BBB) during the first week after surgery. BBB permeability post-surgery was also confirmed in GBM patients. In our murine model, we also observed changes in immune cell morphology and spatial location post-surgery over time in resected Animals as well as the accumulation of reactive microglia and anti-inflammatory macrophages in recurrences compared to unresected tumors since the first steps of recurrence growth. Therefore we investigated whether starting a systemic treatment with the SMAC mimetic small molecule (GDC-0152) directly after surgery would be beneficial for enhancing microglial anti-tumoral activity and decreasing the number of anti-inflammatory macrophages around the GemC12-LNC hydrogel-loaded tumor cavity. The immunomodulatory effects of this drug combination was firstly shown in patient-derived tumoroids. Its efficacy was confirmed in vivo by survival analysis and correlated with reversal of the immune profile as well as delayed tumor recurrence.This comprehensive study identified critical time frames and immune cellular targets within the SMe, aiding in the rational design of combination therapies to delay recurrence onset. Our findings suggest that post-surgical systemic injection of GDC-0152 in combination with GemC12-LNC local treatment is a promising and innovative approach for managing GBM recurrence, with potential for future translation to human patient.

Keywords

Brain tumor surgery; Drug Delivery; Glioblastoma; Neuro-oncology; Targeted therapy; Tumor microenvironment.

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