Lucrezia Principi (Otelfingen / CH), Sebastian Oehler (Otelfingen / CH), Teresa Hemmerle (Otelfingen / CH), Domenico Ravazza (Otelfingen / CH), Dario Neri (Sovicille / IT; Zurich / CH), Ettore Gilardoni (Otelfingen / CH)
Glioblastoma is the most common and deadliest primary brain malignancy in adults, with a median survival of only 16 months from diagnosis. Chemotherapy with Lomustine is currently the standard of care treatment for glioblastoma at progression with a median progression-free survival of only 1.5 months. Novel therapeutic approaches are urgently needed.
L19TNF is a fully human tumor-targeting antibody-cytokine fusion protein, consisting of TNF fused to the L19 antibody, specific to the EDB domain of fibronectin. Phase I and II clinical trials of L19TNF for newly diagnosed glioblastoma or at recurrence are ongoing, investigating the benefit for the patients.
Drug-specific response biomarkers might substantially shorten clinical development time and increase the success rate at the latest phase. Mass spectrometry (MS)-based proteomics is a potent tool for the in-depth analysis of the plasma proteome. To support response assessment and to improve the decision-making processes in clinical drug development, we are developing an LC-MS-based plasma proteomic approach for the discovery of pharmacodynamic biomarkers and immune modulation effects of L19TNF in glioblastoma patients.
Several methodological parameters to identify the suitable conditions for our instruments and the clinical goals were investigated. Particularly, plasma depletion or enrichment during sample preparation is being evaluated to understand the benefits or the disadvantages compared to neat plasma analysis. Moreover, a dedicated Data Independent Acquisition method is being developed. Instrument parameters are being investigated to increase the sensitivity, precision, and total number of quantified proteins.
The best combination of sample preparation and data analysis parameters will be used to perform exploratory studies in mice models to validate the platform developed and in clinical samples to monitor the drug response of Glioblastoma patients.