Immunocytokines are a promising immunotherapeutic approach against glioblastoma

AUTHORS

Tobias Weiss, Emanuele Puca, Manuela Silginer, Teresa Hemmerle, Shila Pazahr, Andrea Bink, Michael Weller, Dario Neri, and Patrick Roth.

SUMMARY

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.

REFERENCES

Tobias W., Emanuele P., Manuela Si., et al. Immunocytokines are a promising immunotherapeutic approach against glioblastoma. Science Translational Medicine 07 Oct 2020: 12, (564), eabb2311 DOI: 10.1126/scitranslmed.abb2311

PRODUCT HIGHLIGHTS

The following Bio X Cell in vivo monoclonal antibodies were featured in the publication:

• anti-mouse CD4 (Clone GK1.5, Bio X Cell catalog no. BP0003-1, BE0003-1)
• rat IgG2b isotype control, anti-keyhole limpet hemocyanin (Clone LTF-2, Bio X Cell catalog no. BP0090, BE0090)
• InVivoanti-mouse CD8 (Lyt 2.1)(Clone 116-13.1 (HB129)), Bio X Cell catalog no. BE0118)
• InVivoMAb mouse IgG2a isotype control, unknown specificity (Clone C1.18.4 Bio X Cell catalog no. BE0085)