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Scientific result | Cancer | Medical imaging | Positron Emission Tomography
Researchers from BioMaps (SHFJ), in collaboration with Baobab (NeuroSpin) and SIMoS (DMTS), have demonstrated the impact of transient BBB permeabilization on brain exposure to an anti-EGFR monoclonal antibody by PET (positron emission tomography) imaging using a radiolabeled antibody (immunoPET). These first results open promising perspectives for targeted immunotherapy of glioblastoma.
The EGFR (epithelial growth factor receptor) signaling pathway controls the oncogenic and metastatic progression of many peripheral and central nervous system (CNS) cancers. Monoclonal antibodies to EGFR such as cetuximab are quite effective in colorectal, head and neck and lung cancers. EGFR is a promising target for the treatment of glioblastoma, the most common malignant brain tumors in adults. However, clinical trials using cetuximab have not shown significant improvement, which is explained by the insufficient brain penetration of cetuximab across the blood-brain barrier (BBB), the main biological interface between the bloodstream and the CNS.
A possible strategy to improve the efficacy of cetuximab in gliobastoma would be to transiently permeabilize the BBB via the combined use of focused ultrasound (FUS) and microbubbles, a technique under development, notably by a team at Baobab (NeuroSpin). In the preclinical study, researchers from the Joliot Institute (SHFJ, NeuroSpin and DMTS) took advantage of immunoPET, which allows the in vivo pharmacokinetic study of radiolabeled antibodies. This approach allowed to evaluate the relevance and the impact of BBB permeabilization by FUS on cetuximab brain penetration and exposure parameters.
For this purpose, 89Zr-labeled cetuximab was injected into mice with or without transient BBB permeabilization by FUS. A longitudinal (7-day) PET imaging study was then performed on these animals. The results obtained show that the use of FUS induces a drastic increase in the transfer of 89Zr-cetuximab from the blood to the brain, followed by a prolonged exposure of the brain tissue to 89Zr-cetuximab.
This preclinical study underlines the interest of FUS as a method of delivering monoclonal antibodies to the CNS. Further studies using animal models of glioblastoma will be necessary to confirm the therapeutic relevance of FUS for targeted immunotherapy of glioblastoma.
Impact of blood-brain barrier permeabilization induced by ultrasound associated to microbubbles on the brain delivery and kinetics of cetuximab: An immunoPET study using 89Zr-cetuximab | Journal of Controlled Relase, 2020
V. Long Tran, A. Novell, N. Tournier, M. Gerstenmayer, A. Schweitzer-Chaput, C. Mateos, B. Jego, A. Bouleau, H. Nozach, A. Winkeler, B. Kuhnast, B. Larrat, C. Truillet
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