Despite recent advances, there are still many patients who don’t respond to current treatments for common blood cancers such as lymphoma. Southampton researchers have made a discovery that could lead to more effective treatments.
'Gold standard'
The current ‘gold standard’ treatment for lymphoma is a monoclonal antibody drug called Rituximab, which has been used to treat over a million patients. Despite its success, Rituximab doesn’t work for all patients and some develop resistance to it. Researchers at Southampton have been pioneering new types of antibody treatments to find an alternative. Monoclonal antibody treatments such as Rituximab harness a natural process to kill cancer: antibodies are produced naturally by the body to attack foreign substances, or pathogens, such as invading bacteria and viruses. Monoclonal antibodies are made in the lab from one ‘parent’ B-cell – a type of white blood cell – so that they are all identical and can be tested for different properties.
The Southampton team has discovered that new ‘type II’ monoclonal antibodies are five times more effective at killing lymphoma cells than current ‘type I’ drugs, such as Rituximab. The research is led by Professor Mark Cragg and Professor Martin Glennie from the Cancer Sciences Division, with funding from Leukaemia & Lymphoma Research, Tenovus, Cancer Research UK and the Medical Research Council. Mark, who was recently awarded a Chair in Experimental Cancer Biology at Southampton, says: “Everyone has antibodies in their circulation and we are using these antibodies to target cancer cells.
Although this idea has been around for over 30 years, it is only now that we are learning how to target the antibodies much more efficiently and discovering new and interesting ways to use the antibodies to kill cancer cells. “Chemotherapy has a lot of toxic side-effects, whereas by using antibodies we can attack tumour cells in ways that are much less toxic to the other cells in the body. Blood tumour cells develop resistance to chemotherapy but they still seem to be sensitive to antibodies, which is one of the reasons we are so interested in using them.”
The Southampton researchers were the first in the world to classify monoclonal antibodies that target a specific molecule known as CD20 into two types: I and II; the findings have been published in several high-profile journals, including The Journal of Clinical Investigation and Blood. They discovered that although type I monoclonal antibodies bind to more receptors and can ‘hack into’ cancer cells by causing calcium signalling to trigger cellular processes in the target cells, they are also removed from the cell surface soon after binding to it. In contrast, type II monoclonal antibodies do none of these things but are better at triggering cell death and staying attached to the target cells after binding
The team
The team has performed a variety of experiments in transgenic mice that express the human CD20 molecule, looking at the dose of monoclonal antibody that would delete a certain proportion of the target cells. They found that they needed only a fifth of type II monoclonal antibody to get the same effect as a type I treatment. Mark comments: “The biggest challenge in carrying out this research was trying to find out why type II monoclonal antibodies work better. Existing dogma says that CD20 antibodies do not get removed from the cell surface, but this was purely based on studies on cell lines that have been cultured in vitro for decades.
“It was only when we examined fresh primary cells straight from cancer patients and looked in vivo with the transgenic mice that we realised that cells can remove type I but not type II monoclonal antibodies from their surface – and that this is the reason why type II treatments work better: they stay attached to the target cells and so are more effective at killing them.”
The Southampton team brings together clinical, scientific and technical expertise, and includes scientists, research assistants, clinicians, clinician scientists, PhD students, medical students and core support staff from the biomedical imaging unit. The team is also working in partnership with Leiden University in Holland and the University of Manchester. Mark, who completed his PhD at the University of Southampton, says: “I chose Southampton for its history, expertise and the facilities that are in place for developing antibody therapy. Southampton is a fantastic place for taking basic science and putting it into practice.
“With a Cancer Research UK clinical centre, several centres of excellence sponsored by other cancer charities and international experts in different aspects of immunology, we have the ability and resources to translate findings into clinical practice. Southampton is unusual in having all of these different elements in place.” One of the type II monoclonal antibodies the team studied, known as GA101, is currently in phase I/II clinical trials in 20 centres worldwide, including Southampton. If this treatment is proven to be successful, GA101 could be available within a few years. Mark hopes that more trials like this will follow and he and his team are considering developing their own treatment for clinical use.
Over the next five years, the team aims to develop a new range of antibodies that are even more effective than Rituximab to improve survival rates of people with lymphoma.
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