Research ArticleCancer

Immunocytokines are a promising immunotherapeutic approach against glioblastoma

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Science Translational Medicine  07 Oct 2020:
Vol. 12, Issue 564, eabb2311
DOI: 10.1126/scitranslmed.abb2311

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Make way for cytokines

Glioblastoma is an aggressive and frequently lethal brain malignancy, which is usually resistant to both conventional and immune-based therapies. To promote immune responses against this cancer, Weiss et al. designed fusion molecules that deliver cytokines directly to the tumors after systemic administration. To do this, the authors combined an antibody against a glioblastoma-specific stromal protein with two different immunostimulatory cytokines. The resulting fusion proteins could be delivered intravenously and accumulate in the tumors, showing promising results in mouse models and in a pilot trial in human patients.

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.

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