Scientists at UCL have developed a novel therapeutic antibody that can unblock blood vessels inside tumours to allow for more effective drug delivery of targeted cancer treatments.
Blood vessels in tumour development
Promoting angiogenesis (the formation of blood vessels) is one of the key hallmarks of cancer. It has long been recognised as an essential feature for tumour expansion, survival and metastatic spread. As such, targeting pro-angiogenesis signalling molecules, such as VEGF, to limit vascular growth has become a key therapeutic regimen. Although these therapies have seen some success, they have had little impact on overall survival rates.
Poorly functioning tumour vessels have also been shown to promote pro-oncogenic environments and limit the administration of cancer drugs. As a result, an alternative strategy has arisen that aims to normalise the vasculature and make the microenvironment more conducive to tumour destruction.
Previous work has shown that LRG1, a secreted glycoprotein, is associated with abnormal vessel growth in various diseases. Researchers have shown that LRG1 is induced in many carcinomas and raised levels of this glycoprotein in the blood have been correlated with a poor prognosis.
In a recent study, published in Med, researchers aimed to establish whether LRG1 affected tumour vessel structure and function. Most importantly, they also wanted to explore the implications of this on therapy. The researchers specifically used genetically engineered wild-type and Lrg1 knockout mice to analyse tumour growth and vascular structures. They also explored the effects of LRG1 antibody blockade as monotherapy or in combination with co-therapies.
The team found that LGR1 affected vessel growth, structure and function. By deleting Lrg1 in mice or blocking its function with a targeted antibody, the researchers observed reduced tumour growth. They also demonstrated that tumour vessels exhibited a more normalised state with improved vascular function and endothelial cell pericyte coverage. This resulted in enhanced efficacy of cisplatin chemotherapy, adoptive T cell therapy and immune checkpoint inhibitor therapy. Inhibition of LRG1, in the context of immunotherapy, led to a significant change in the tumour microenvironment from being predominantly immune silent to immune active.
Co-lead author, Professor Stephen Moss, said:
“Although counterintuitive, finding a way to normalise cancerous tumour blood vessels has become a clinical objective, but identifying an effective therapeutic tool has proven elusive.
Our results provide direct evidence that blocking the LRG1 protein, which is produced at high levels in tumours, normalises the vasculature and enhances the current sub-optimal effectiveness of immunotherapies, including checkpoint inhibition and CAR-T cell therapy, in solid cancers.
This opens up the potential to achieve a far better result in many cancer patients who respond poorly to current standard of care.”
The research team have developed a human version of the LRG1-blocking antibody – Magacizumab – that is now ready to progress to clinical trials in patients with cancer and eye disease.
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