Managing toxicity when treating cancer with next-generation drugs

Researchers at the University of Liverpool are researching the newest next-generation drugs – actual biological structures themselves that bind to and stimulate the immune system – to treat patients with more advanced, malignant cancers and dealing with the toxicity that can accompany these novel therapies.

Every person dreads cancer. Half of men and 45% of women in the UK will get a diagnosis in their lifetime, and despite billions spent many people do not respond well to conventional treatments.

The challenge

“We’re trying to understand and overcome the defence mechanisms that malignant cancers put in place, to allow the person’s immune system to attack cancer cells,” says Dr Anna Olsson-Brown at the University’s Institute of Translational Medicine. The new drugs are monoclonal antibodies (MCAs, or MABs) and work by recognising and locking onto specific proteins on tumours. The new immunotherapy drugs stimulate the immune system by inhibiting the checkpoint proteins that keep the immune response in check. In effect, it’s like taking the brakes off the cancer’s defences and reinstating the protection the immune system puts in place to prevent cancer in the first place.

The five MCA drugs (nivolumab, pembrolizumab, ipilimumab, atezolizumab and avelumab) now approved by UK regulator NICE can be extremely effective. However they can provoke strong toxic reactions as the person’s immune system bounces back, causing conditions such as hepatitis, colitis, endocrine dysfunction, arthritis and skin toxicity. Complicating matters further is the relative lack of in-depth data compared to older treatments, so the book on how much drug to prescribe and when for the best patient outcome is still being written.

Our research

In this multi-billion-dollar industry, Olsson-Brown is especially interested in predicting if, and how severe, toxicity might be for individual patients and how that will affect their treatment outcomes and the morbidity/mortally associated with the toxicity. Perhaps counter intuitively toxicity is seen in patients that get good responses, but it is not a requirement for response suggesting the relationship between response and toxicity is more complex than it first appears. “There are a number of reasons a person may get toxicity, for instance a latent auto-immune disorder awakened by the therapy, and the combination of those factors is likely to relate to the propensity for toxicity to occur,” she says.

Olsson-Brown and colleagues are identifying biomarkers to predict who will get what type of toxicity, relating that to their future outcomes. Answering these questions will take years, but the benefits could be staggering because managing toxicity to allow comprehensive treatment to be given allows people to be cured – and stay cured. In theory, immunotherapy could be used to treat any cancer, not just the metastatic melanoma, non-small cell lung cancer, kidney, head and neck cancers that are the current focus. “It’s conceivable that immunotherapies could be used as part of the treatment pathway in most malignancies within the next ten years,” says Olsson-Brown.

An excellent place to do research

Part of the University’s personalised health research, Olsson-Brown makes extensive use of the benefits available at Liverpool, such as expertise at the MRC Centre for Drug Safety Science. In addition, she has established the Merseyside and Cheshire immuno-oncology clinical network, access to nurses with special experience with immune therapy patients, and a research team for recruiting patients. International collaborations include utilising expertise in the European and American oncological societies, as well as large, ongoing clinical trials and industrial fellowships with the major pharmaceutical manufacturers Roche, Ely Lilly, USP and Novartis

Liverpool’s Department of Molecular and Clinical Pharmacology was awarded a Queen’s Anniversary Prize in 2017 for its work to improve the safety and effectiveness of medicines.