The leaky, disorganized mess of blood vessels that support tumors can stop drugs from reaching their targets and thereby nullify their impact. Recognizing that, researchers have identified a way to bring order to the blood vessels—and thereby enable drugs to reach their targets in the tumor.
Over the years, researchers have explored alternative uses for drugs such as Avastin, using low doses of the molecules to normalize the vasculature and enable other molecules to penetrate tumors. The application marks a departure from the original use of the drugs, which were designed to stop the growth of vessels and thereby prevent blood from supplying tumors, but has yielded positive data.
The progress encouraged a team at University College London (UCL) to explore other ways to modify the tumor vasculature, leading to the study of an antibody against a protein associated with abnormal vessel growth. Levels of the protein, LRG1, correlate with increased tumor load and poor prognosis.
Writing in the journal MED, the researchers show LRG1 antibody blockade or gene deletion results in more stable, physiologically functional tumor vessels in mice. Combining the anti-LRG1 antibody with cisplatin chemotherapy, adoptive T-cell therapy or a checkpoint inhibitor lead to better results than was achieved by the established interventions as single agents.
“Our results provide direct evidence that blocking the LRG1 protein, which is produced at high levels in tumors, normalizes 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,” UCL’s Stephen Moss, Ph.D., co-lead author of the paper, said in a statement.
The researchers have developed a human version of the LRG1-blocking antibody magacizumab and spun out the technology to create PanAngium Therapeutics. PanAngium is exploring the use of the molecule in the treatment of ophthalmic diseases associated with pathological neovascularization.