Novel drug liberates tumor vessels to aid cancer drug delivery

A therapeutic antibody developed by scientists at UCL has been shown to unblock and normalize blood vessels inside cancerous tumors, enabling the more effective delivery of targeted cancer treatments.

The findings in mice, published in the journal Med, are the first to demonstrate that inhibiting the activity of LRG1, a protein produced in many tumorous tissues, liberates disorganized angiogenesis (blood vessel formation)—a leading cause of morbidity in numerous diseases including cancer.

Researchers say the novel drug offers the potential to achieve a far better outcome in patients who respond poorly to current standard of care for cancers, including those of the breast, colon, bladder, prostate, and lung.

Furthermore, researchers also found the antibody significantly enhanced the ability of immunotherapies to reduce solid tumors, including cancers resistant to immune checkpoint inhibitors and CAR T-cell therapy, something that clinicians and scientists have struggled to overcome.

Explaining the study, co-lead author, Professor John Greenwood (UCL Institute of Ophthalmology) said: “Cancers need a blood supply to grow, but when new vessels form inside a tumor they are typically abnormal, resulting in compromised oxygen delivery that may render the tumor more aggressive.

“This impaired blood supply also limits the delivery of therapies reducing their effectiveness and contributing to treatment resistance. We asked whether blocking the activity of a novel molecule that damages blood vessels, namely LRG1, would allow vessels to grow more normally thus reducing tumor expansion and, most importantly, enhancing the delivery and efficacy of other drugs.”

For the study, a UCL-developed LRG1-blocking antibody was administered to tumor-bearing mice in the presence and absence of various cancer therapeutics, simulating similar treatment courses as found in humans.

In the models of cancer examined, the antibody, when used alone (monotherapy), significantly improved blood flow and oxygenation and reduced tumor growth rates. When combined with chemotherapy, or new immunotherapies which have shown less utility in solid tumors, such as carcinomas and glioblastomas, there was an increase in immune cell infiltration and tumor cell killing activity inside the tumor compared to monotherapy.

Co-lead author Professor Stephen Moss (UCL Institute of Ophthalmology) said: “Although counterintuitive, finding a way to normalize cancerous tumor 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 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.”