Permeabilisation of brain metastases for early and more effective treatment

The spread of cancer from a primary tumour to the brain remains one of the greatest challenges in cancer treatment, and life expectancy from diagnosis is typically 3-9 months. Blood vessels in the brain are much less permeable than those elsewhere in the body and possess what is known as the blood-brain barrier, which prevents the movement of drugs from the blood into the brain. This blood-brain barrier is one of the main reasons why early treatment of secondary brain tumours (metastases) is not possible. However, we know that the earlier treatment begins, the more effective it is likely to be. We are interested, therefore, in finding ways to make the blood vessels close to brain metastases leaky, particularly when they are still very small.

We have recently shown in experimental models that by injecting a protein called TNF into the blood we can make the vessels close to brain metastases leaky, whilst leaving the rest of the vessels in the brain intact. This approach works because the blood vessels associated with these secondary tumours are different to normal brain blood vessels and express a protein receptor (TNFR1). TNF is able to interact with this receptor and, in doing so, causes the vessels to become leaky. We have shown that using this approach we can selectively deliver common cancer therapies to brain metastases when they are still very small.

TNF can be toxic at high doses, but the amounts we are using are much lower than this and, therefore, would be tolerable. Nevertheless, by developing a more selective protein that interacts only with TNFR1, and no other protein receptors, we have been able to further decrease the amount needed and reduce the likelihood of toxic side-effects. We now aim to show that it is possible to increase delivery of a clinically used drug into brain metastases by administering it together with the new TNFR1-selective protein, and that the therapeutic effect of the drug is enhanced as a consequence. Next we will optimise production of the TNFR1-selective protein for human use and undertake pre-clinical toxicology and stability tests to support a downstream clinical trial. We also aim to show that our approach to making vessels in brain metastases leaky is effective for several different tumour types (breast, lung and melanoma), all of which are at high risk of spreading to the brain, to further support clinical translation.

The huge advantage of this approach to overcoming the blood-brain barrier, compared to alternative solutions, is that delivery of any therapeutic drug to these tiny brain tumours is possible once the vessels are leaky. At the end of this project, we will be ready to apply for authorisation to undertake an early phase clinical trial; within this trial we will obtain preliminary information on whether our TNFR1-selective protein enables improved treatment of brain metastases.

Metastasis to the brain is a major challenge in cancer therapy and prognosis is poor. The blood-brain barrier (BBB) is a significant impediment to both early detection and effective treatment, as it is intact during the early stages of tumour development and only heterogeneously permeable at later stages. The presence of an intact BBB excludes both therapeutic and diagnostic imaging agents from metastases. However, we have shown in mouse models that intravenous injection of the cytokine tumour necrosis factor (TNF) selectively permeabilises the BBB at sites of micrometastases in the brain, leaving the rest of the BBB intact. This permeabilisation is mediated primarily though activation of the TNF type 1 receptor (TNFR1), and it enables delivery of otherwise excluded therapies. Whilst we have demonstrated that the permeabilising activity of TNF occurs at concentrations below the maximum tolerated dose, we have now developed a TNFR1-selective mutein (mutTNF) that will reduce the required dose even further and eliminate toxicity associated with activation of other TNF receptors. We have demonstrated binding specificity and permeabilising action of the mutTNF, in vitro and in vivo, and have obtained preliminary toxicology data showing no contraindications to clinical translation. We now propose to (i) demonstrate enhanced delivery and efficacy of a clinically relevant drug in mouse models of brain metastasis when combined with mutTNF administration, (ii) develop the mutTNF production for human use, (iii) undertake pre-clinical toxicology and stability trials, (iv) produce a clinic-ready CTA package, and (v) demonstrate permeabilisation in additional models of micro- and macrometastasis to support clinical translation. At the end of this project, we will be ready to undertake a Phase I/IIa clinical trial. Our solution to the problem of an intact BBB in brain metastasis, will open a treatment window that currently does not exist in a substantial number of cancer patients.