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Brain intratumoural astatine-211 radiotherapy targeting syndecan-1 leads to durable glioblastoma remission and immune memory in female mice.
Roncali, Loris; Marionneau-Lambot, Séverine; Roy, Charlotte; Eychenne, Romain; Gouard, Sébastien; Avril, Sylvie; Chouin, Nicolas; Riou, Jérémie; Allard, Mathilde; Rousseau, Audrey; Guérard, François; Hindré, François; Chérel, Michel; Garcion, Emmanuel.
Afiliación
  • Roncali L; Université d'Angers, INSERM, CNRS, CRCI(2)NA, F-49000, Angers, France; Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France.
  • Marionneau-Lambot S; Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France; CHU Nantes, Nantes Université, Service de médecine nucléaire, F-44000, Nantes, France; CIMA (Centre d'Imagerie Multimodale Appliquée), Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France.
  • Roy C; Université d'Angers, INSERM, CNRS, CRCI(2)NA, F-49000, Angers, France; PRIMEX (Plateforme de Radiobiologie et d'Imageries Expérimentales), Université d'Angers, SFR 4208, F-49000, Angers, France.
  • Eychenne R; Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France; GIP ARRONAX, F-44160, Saint-Herblain, France.
  • Gouard S; Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France; CIMA (Centre d'Imagerie Multimodale Appliquée), Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France.
  • Avril S; Université d'Angers, INSERM, CNRS, CRCI(2)NA, F-49000, Angers, France.
  • Chouin N; Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France; ONIRIS, F-44000, Nantes, France.
  • Riou J; CHU Angers, Université d'Angers, F-49000, Angers, France.
  • Allard M; Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France.
  • Rousseau A; Université d'Angers, INSERM, CNRS, CRCI(2)NA, F-49000, Angers, France; CHU Angers, Université d'Angers, F-49000, Angers, France.
  • Guérard F; Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France.
  • Hindré F; Université d'Angers, INSERM, CNRS, CRCI(2)NA, F-49000, Angers, France; PRIMEX (Plateforme de Radiobiologie et d'Imageries Expérimentales), Université d'Angers, SFR 4208, F-49000, Angers, France.
  • Chérel M; Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France; CIMA (Centre d'Imagerie Multimodale Appliquée), Nantes Université, INSERM, CNRS, CRCI(2)NA, F-44000, Nantes, France; Institut de Cancérologie de l'Ouest, Service de médecine nucléaire, F-44160, Saint-Herblain, France. Electronic ad
  • Garcion E; Université d'Angers, INSERM, CNRS, CRCI(2)NA, F-49000, Angers, France; PRIMEX (Plateforme de Radiobiologie et d'Imageries Expérimentales), Université d'Angers, SFR 4208, F-49000, Angers, France; PACEM (Plateforme d'Analyse Cellulaire et Moléculaire), Université d'Angers, SFR 4208, F-49000, Angers, F
EBioMedicine ; 105: 105202, 2024 Jul.
Article en En | MEDLINE | ID: mdl-38905749
ABSTRACT

BACKGROUND:

Glioblastoma (GB), the most aggressive brain cancer, remains a critical clinical challenge due to its resistance to conventional treatments. Here, we introduce a locoregional targeted-α-therapy (TAT) with the rat monoclonal antibody 9E7.4 targeting murine syndecan-1 (SDC1) coupled to the α-emitter radionuclide astatine-211 (211At-9E7.4).

METHODS:

We orthotopically transplanted 50,000 GL261 cells of murine GB into the right striatum of syngeneic female C57BL/6JRj mice using stereotaxis. After MRI validation of tumour presence at day 11, TAT was injected at the same coordinates. Biodistribution, efficacy, toxicity, local and systemic responses were assessed following application of this protocol. The 9E7.4 monoclonal antibody was labelled with iodine-125 (125I) for biodistribution and with astatine-211 (211At) for the other experiments.

FINDINGS:

The 211At-9E7.4 TAT demonstrated robust efficacy in reducing orthotopic tumours and achieved improved survival rates in the C57BL/6JRj model, reaching up to 70% with a minimal activity of 100 kBq. Targeting SDC1 ensured the cerebral retention of 211At over an optimal time window, enabling low-activity administration with a minimal toxicity profile. Moreover, TAT substantially reduced the occurrence of secondary tumours and provided resistance to new tumour development after contralateral rechallenge, mediated through the activation of central and effector memory T cells.

INTERPRETATION:

The locoregional 211At-9E7.4 TAT stands as one of the most efficient TAT across all preclinical GB models. This study validates SDC1 as a pertinent therapeutic target for GB and underscores 211At-9E7.4 TAT as a promising advancement to improve the treatment and quality of life for patients with GB.

FUNDING:

This work was funded by the French National Agency for Research (ANR) "France 2030 Investment Plan" Labex Iron [ANR-11-LABX-18-01], The SIRIC ILIAD [INCa-DGOS-INSERM-18011], the French program "Infrastructure d'Avenir en Biologie-Santé" (France Life Imaging) [ANR-11-INBS-0006], the PIA3 of the ANR, integrated to the "France 2030 Investment Plan" [ANR-21-RHUS-0012], and support from Inviscan SAS (Strasbourg, France). It was also related to the ANR under the frame of EuroNanoMed III (project GLIOSILK) [ANR-19-ENM3-0003-01]; the "Région Pays-de-la-Loire" under the frame of the Target'In project; the "Ligue Nationale contre le Cancer" and the "Comité Départemental de Maine-et-Loire de la Ligue contre le Cancer" (CD49) under the frame of the FusTarG project and the "Tumour targeting, imaging and radio-therapies network" of the "Cancéropôle Grand-Ouest" (France). This work was also funded by the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Nantes, and the University of Angers.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Astato / Glioblastoma / Sindecano-1 Límite: Animals / Female / Humans Idioma: En Revista: EBioMedicine Año: 2024 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Astato / Glioblastoma / Sindecano-1 Límite: Animals / Female / Humans Idioma: En Revista: EBioMedicine Año: 2024 Tipo del documento: Article País de afiliación: Francia