Related Experiment Video
Updated: Dec 6, 2025
Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts
Published on: September 1, 2018
Immunocytokines are a promising immunotherapeutic approach against glioblastoma
Tobias Weiss1, Emanuele Puca2, Manuela Silginer1
1Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, CH-8091 Zurich, Switzerland.
Abstract:
Glioblastoma is a poorly immunogenic cancer, and the successes with recent immunotherapies in extracranial malignancies have, so far, not been translated to this devastating disease. Therefore, there is an urgent need for new strategies to convert the immunologically cold glioma microenvironment into a hot one to enable effective antitumor immunity. Using the L19 antibody, which is specific to a tumor-associated epitope of extracellular fibronectin, we developed antibody-cytokine fusions-immunocytokines-with interleukin-2 (IL2), IL12, or tumor necrosis factor (TNF). We showed that L19 accumulated in the tumor microenvironment of two orthotopic immunocompetent mouse glioma models. Furthermore, intravenous administration of L19-mIL12 or L19-mTNF cured a proportion of tumor-bearing mice, whereas L19-IL2 did not. This therapeutic activity was abolished in RAG-/- mice or upon depletion of CD4 or CD8 T cells, suggesting adaptive immunity. Mechanistically, both immunocytokines promoted tumor-infiltrating lymphocytes and increased the amounts of proinflammatory cytokines within the tumor microenvironment. In addition, L19-mTNF induced tumor necrosis. Systemic administration of the fully human L19-TNF fusion protein to patients with glioblastoma (NCT03779230) was safe, decreased regional blood perfusion within the tumor, and was associated with increasing tumor necrosis and an increase in tumor-infiltrating CD4 and CD8 T cells. The extensive preclinical characterization and subsequent clinical translation provide a robust basis for future studies with immunocytokines to treat malignant brain tumors.
Insights
New immunocytokines targeting glioblastoma show promise. L19-IL12 and L19-TNF therapies activated antitumor immunity in mice and were safe in human trials, increasing tumor necrosis and T cell infiltration.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Glioblastoma is a highly aggressive brain tumor with a poor prognosis.
- Current immunotherapies have limited success in glioblastoma due to its cold, immunologically inactive tumor microenvironment.
- Novel strategies are needed to enhance anti-tumor immune responses in glioblastoma.
Purpose of the Study:
- To develop and evaluate novel immunocytokines for glioblastoma treatment.
- To investigate the therapeutic efficacy and underlying mechanisms of L19-based immunocytokines.
- To assess the safety and preliminary efficacy of L19-TNF in human glioblastoma patients.
Main Methods:
- Development of antibody-cytokine fusions (immunocytokines) using the L19 antibody targeting fibronectin, fused with interleukin-2 (IL2), IL12, or tumor necrosis factor (TNF).
- Evaluation in orthotopic immunocompetent mouse glioma models, including assessments in RAG-/- mice and T cell depletion studies.
- Clinical trial (NCT03779230) involving systemic administration of L19-TNF in glioblastoma patients.
Main Results:
- L19 immunocytokines accumulated in the glioma microenvironment.
- L19-mIL12 and L19-mTNF demonstrated significant therapeutic activity in mice, leading to cures in a proportion of animals.
- Therapeutic effects were dependent on adaptive immunity (T cells).
- In patients, L19-TNF was safe, reduced tumor perfusion, and increased tumor necrosis and infiltration of CD4+ and CD8+ T cells.
Conclusions:
- L19-based immunocytokines, particularly L19-mIL12 and L19-mTNF, can overcome the immunosuppressive glioblastoma microenvironment.
- These agents activate adaptive anti-tumor immunity, leading to significant therapeutic benefits in preclinical models.
- The promising safety and preliminary efficacy data in human patients support further clinical investigation of immunocytokines for malignant brain tumors.
Related Concept Videos
01:27Tumor Immunotherapy
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
01:30Cancer Vaccines
Cancer vaccines come in two categories: preventive (prophylactic) and treatment (active). Preventive vaccines, such as the Human Papillomavirus (HPV) vaccine, protect against viruses that cause certain...