Metastatic spread to the brain

Brain metastasis is one of the greatest hurdles in cancer therapy. 20-40% of all cancer patients will suffer metastatic spread of the primary cancer to the brain. Unfortunately, our inability to treat brain metastases at a sufficiently early stage is a major limitation in cancer patient outcome. Clinical diagnosis and treatment are limited to larger, late-stage metastases (>5mm) and early treatment (<5mm) remains challenging.

Whilst the blood-brain barrier is essential for protecting the brain against the invasion of unwanted molecules, it also blocks the passage of therapeutic agents, presenting a limitation to the early treatment of brain metastases, where the blood-brain barrier is still intact.

Oxford Invention

To address this challenge, Oxford researchers have engineered a small protein, mutTNF, that selectively permeabilises the blood-brain barrier at sites of brain metastases and facilitates the specific delivery of tumour chemotherapies to these small, early-stage tumours. The invention has the potential to extend current brain metastasis treatment options without needing prior knowledge of tumour location or needing to modify existing cancer drugs.

Supporting Data

The research has demonstrated that:

1. mutTNF can be used to temporarily and reversibly increase blood-brain barrier permeability at sites of brain metastases and, thus, enables the delivery of anti-cancer drugs and imaging agents to the brain.
2. mutTNF binds specifically to the TNFR1 receptor, which is only present on blood vessels at the site of a metastatic cancer in the brain; consequently, mutTNF selectively permeabilises the vasculature at tumour sites and normal vasculature remains intact.
3. mutTNF is highly selective for TNFR1 and exhibits low immunogenicity, which reduces off-target effects and toxicity.
4. mutTNF administration enhances focal delivery of the anti-breast cancer antibody Herceptin^® to brain metastases in mouse models.

Patent Position

The invention is subject to two patents: first, on the use of TNF as permeabilising agent of intact tumour vasculature for treatment and detection of CNS tumours (granted in EU, pending in US); and second, a composition of matter patent on mutTNF (pending in EU and US).