P06.08.a clinical outcome and translational insights from a phase i/ii trial with the tumor-targeting antibody-cytokine fusion protein l19tnf for patients with recurrent glioblastoma

Abstract BACKGROUND Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. Cytokine-based therapies are promising cancer immunotherapies that potentially can convert an immunologically “cold” tumor microenvironment into a “hot” one and may trigger potent antitumor immunity. However, the systemic administration of pro-inflammatory cytokines at therapeutically active doses is hampered by toxic side effects. L19TNF is a fully human antibody-cytokine fusion protein, comprising tumor necrosis factor (TNF) fused to the antibody L19 that binds a tumor-specific epitope of fibronectin. This allows targeted delivery of relevant doses of TNF to the tumor while sparing healthy organs. Here, we report the results of a clinical trial with systemically administered L19TNF as monotherapy for patients with recurrent glioblastoma. MATERIAL AND METHODS NCT03779230 was an open-label, non-randomized, multicenter phase I/II clinical trial to investigate the safety and preliminary efficacy of L19TNF monotherapy for patients with IDH-wildtype WHO grade 3/4 glioma at first relapse. L19TNF was administered intravenously in three-week cycles. Tumor responses were assessed by iRANO criteria. Accompanying translational research comprised longitudinal analyses of MRI scans using automated segmentation as well as for five matched paired samples obtained before and after L19TNF tissue immunophenotyping using imaging mass cytometry and mass spectrometry-based proteomics to characterize immunological and molecular effects of the treatment. RESULTS From 2019 - 2020, we enrolled 20 patients (19 WHO Grade 4 and 1 WHO grade 3) from three centers in Switzerland; tumors of 17 patients (85%) had a prognostically unfavorable unmethylated MGMT promoter status. L19TNF could be safely administered at a dose of 13 µg/kg and we did not observe severe adverse events. The median progression-free survival was 2.0 months and the median overall survival was 10.9 months. Using MRI imaging including perfusion maps, we observed that L19TNF led to treatment-associated tumor necrosis within one week of the treatment. Imaging mass cytometry and proteomics from five matched paired samples obtained before and after L19TNF revealed immunophenotypic and molecular changes in tumor tissue, indicating the induction of an anti-tumor immune response and alterations of multiple non-immunological pathways (transcription, translation, cell cycle, proliferation). CONCLUSION The intravenous administration of L19TNF is safe in patients with recurrent glioblastoma and shows pharmacodynamic effects at the tumor site. Ongoing studies investigate L19TNF in combination with temozolomide-based chemoradiation for patients with newly diagnosed glioblastoma (NCT04443010) and in combination with lomustine for patients at first progression (NCT04573192).