IMMU-02. Targeted innovative antibody fragment-based immunotherapy for medulloblastoma. (3rd June 2022)

• Record Type: Journal Article
• Authors: Niesen, Judith; Krüger, Christina; Kreuter, Naomé; Haferkamp, Undine; Pless, Ole; Schüller, Ulrich
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 1
• Page Start: i81
• Page End: i81
• Publication Date: 2022-06-03
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac079.295
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Medulloblastoma (MB) is the most common malignant pediatric brain tumor accounting for ~20 % of childhood brain tumors. One third of all MB are characterized by constitutive activation of the Sonic Hedgehog (SHH)-signaling pathway. This tumor type shows overexpression of the epidermal growth-factor receptor (EGFR), which we detected in SHH-MB patient samples, transgenic SHH MB mouse models, and MB-cell lines. In contrast, non-neoplastic cells only express EGFR at low levels. Intensive radio-/chemotherapy often leaves the young patients with significant long-term burdens including problems in brain development and cognitive deficits. Thus, there is an urgent need to develop new targeted therapies that can prevent tumor recurrence without affecting healthy cells. We selected EGFR as a potential therapy target using EGFR-specific antibody fragments (scFvs) as part of immunoconjugates, namely bispecific T-cell engagers (BiTEs) and immunotoxins (ITs). Both, the EGFR-specific BiTEs and the ITs showed specific binding and cytotoxic activity in MB cells. Effector- and target-cell specificity was demonstrated via flow cytometry for the BiTEs. BiTEs and ITs selectively killed MB-tumor cells and showed pro-apoptotic effects without unspecific effects. Furthermore, preliminary results from an innovative hiPSC-based in vitro-BBB-model suggest, that the ITs are able to cross the BBB. Finally, by having a functional cloning- and expression system for the BiTEs and ITs available, target-scFvs can be easily exchanged by novel antigens or peptides to obtain additional targeted immunotherapies. Together, these results pave the way for preclinical in vivo experiments and future clinical trials in patients with SHH MB.