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, Prof. Sibson and her colleagues 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 (Connell et al., 2013, Journal of the National Cancer Institute). This permeabilisation is mediated primarily though activation of the TNF type 1 receptor (TNFR1), and it enables delivery of otherwise excluded therapies.
Although the permeabilising activity of TNF was shown to occur at concentrations below the maximum tolerated dose, to facilitate clinical translation Prof. Sibson and her colleagues wanted to reduce the potential for toxicity further. To this end, under an initial MRC Developmental Pathway Funding Scheme (DPFS) award, they 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. They have demonstrated binding specificity and permeabilising action of the mutTNF, both in vitro and in vivo, and have obtained preliminary toxicology data showing no contraindications to clinical translation.
On the basis of the above developments, Prof. Sibson together with her co-applicants Prof. Anthony, Dr Campbell and Prof. Middleton have now been awarded a second MRC Developmental Pathway Funding Scheme grant, for £3.3 million, to acquire further preclinical data to support the case for clinical translation, to develop the mutTNF production for human use and to undertake pre-clinical toxicology. At the end of this project, they will be ready to undertake a Phase I/IIa clinical trial in patients with brain metastases.
This 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.