Neuroscience and Neurology

Using antibody-cytokine fusion proteins to combat the most aggressive brain tumour

Dr. Dr. Tobias Weiss

Universitätsspital Zürich
​​​​​​​Universität Zürich

Dr. Emanuele Puca

ETH Zürich

Gliobastoma is the most common and most aggressive primary brain tumour in adults and is incurable to date. Gliobastomas hardly respond to immunotherapies as the tumour microenvironment is immunologically “cold” and suppresses effective immune responses. How can we deliver effective drugs to the tumour and turn a “cold” microenvironment “hot”? Are there molecules that could serve as transport vehicles for bioactive payloads that “find” neoplastic cells and induce an effective anti-tumour immune response?  

The research teams of Tobias Weiss and Emanuele Puca knew that the L19 antibody binds to a tumour-specific protein that is undetectable in healthy tissues, while being highly expressed in glioblastoma. However, such antibody alone is insufficient to combat the disease effectively. They therefore fused the L19 antibody with a pro-inflammatory cytokine, to generate an immunocytokine (L19-TNF) with potent anti-cancer activity. They sent this “armed ferry” to the tumour through the bloodstream which then selectively concentrates at the site of disease to trigger a local immune response.

The Zurich scientists did, indeed, achieve a selective accumulation of the L19 fusion protein in the brain tumour which led to promising long-term tumour eradications in glioma-bearing mice. They have also demonstrated that this strategy fosters a significant elevation of immune cells in the tumour mass, thus turning a “cold” tumour “hot”. On the basis of the promising pre-clinical findings, the collaborators, have started a Phase I/II clinical trial, sponsored by the Swiss-Italian biotech company Philogen. In this trial, the safety and preliminary efficacy of L19-TNF monotherapy is investigated in patients with recurrent Isocitrate dehydrogenase IDH-wildtype WHO grade III/IV glioma. 

In the first patients of this clinical trial, the researchers confirmed the results from animal models: L19-TNF induced a local anti-tumor immune response and in certain tumor areas the cancer cells died.  This laid the foundation for multiple pre-clinical follow up projects and further clinical trials using immunocytokines in combination with conventional cancer therapies for patients with glioblastoma.

Immunocytokines are a promising immunotherapeutic approach against glioblastoma. Tobias Weiss*, Emanuele Puca*, Manuela Silginer, Teresa Hemmerle, Shila Pazahr, Andrea Bink, Michael Weller, Dario Neri, Patrick Roth.
Sci Transl Med. 2020 Oct 7;12(564):eabb2311. doi: 10.1126/scitranslmed.abb2311. 
*These authors contributed equally to this work.