Work

Epidermal growth factor receptor specific immunotherapy for SHH medulloblastoma tested in an in vitro blood-brain barrier-model

Year: 2025

Type: article

Abstract: Despite advances in treating pediatric malignant tumors like SHH-medulloblastoma (SHH-MB), the current standard of care remains surgery followed by chemo- and radiotherapy. This aggressive therapy goes along with a significant morbidity with many long-term side effects, especially in children and adolescents. Therefore, more targeted therapies are urgently needed. Immunotoxins (ITs) conjugated to tumor-antigen specific antibodies have shown potential for selectively targeting tumor cells. In this study, we generated a single chain variable fragment (scFv)-based IT that incorporates a truncated, less immunogenic variant of Pseudomonas Exotoxin A. The IT specifically targets the epidermal growth factor receptor (EGFR), a tumor-associated antigen commonly overexpressed in SHH-MB. We demonstrate that this immunotherapeutic approach reduced tumor cell viability and induced apoptosis in MB-cell lines with IC50 values ranging from 3.1 to 5.3 nM. Given that SHH-MB exhibit dysregulated PI3-kinase (PI3K) pathway signaling, we combined the IT with a PI3K inhibitor. Combination treatment led to dose-dependent reductions in IC50 values (from 2.51 – 13.9 nM at 0.5 µM to 1.01 –3.4 nM at 2 µM). Additionally, we demonstrate that the generated IT can successfully cross the Blood-Brain-Barrier (BBB) in vitro in an in vitro BBB-model based on HBMEC cells. These results suggest that this immunotherapeutic approach is a promising candidate for further development and clinical application.

Source: Cancer Treatment and Research Communications

DOI: 10.1016/j.ctarc.2025.100950