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.