Researchers find that aggressive ‘triple negative’ breast cancers express high levels of folate receptor FRα – and could be targeted with immunotherapy and other antibody approaches.

Monday 17 December 2018      Our research
T cell lymphocyte

Targeted antibody therapies – including a new antibody immunotherapy – could offer “long-awaited” advances for patients with aggressive ‘triple negative’ breast cancer, following the discovery of a new target protein helping to drive the disease’s growth.

In a new study, scientists at the Breast Cancer Now Research Unit at King’s College London found that a significant proportion of highly aggressive triple negative tumours, including those that are resistant to chemotherapy, produce high levels of a protein called folate receptor alpha (FRα).

Importantly, the researchers found that antibody immunotherapies targeting FRα significantly reduced growth of triple negative tumours in mice, priming the immune system to recognise and attack cancer cells.

Triple negative breast cancer – which makes up around 15% of all breast cancers – is so-named for its lack of three key receptors that can be targeted with treatments in other forms of the disease. Treatment options for triple negative patients are therefore usually limited to surgery, as well as chemotherapy and radiotherapy, which can weaken patients’ immune systems.

In recent years, cancers such as melanoma and lymphoma have seen significant breakthroughs in immunotherapy, which involves reprogramming the immune system – the body’s major defence mechanism – to recognise and kill cancer cells. However, to date, immunotherapies that can benefit breast cancer patients have not seen the same success.

With triple negative breast cancers often being more aggressive as well as harder-to-treat than other types of the disease, survival outcomes are often poor for the 7,500 women diagnosed each year in the UK.

In the new study, a team of researchers led by Dr Sophia Karagiannis at King’s College London, first confirmed that FRα – a protein often produced at high levels in ovarian, lung, breast and other types of cancer – plays a crucial role in supporting growth and survival of triple negative breast tumours. The team proposed that FRα could be a suitable target for different antibody treatment approaches.

The team showed that antibodies were able to recognise the FRα receptor in both triple negative breast cancer cells and in patient tumours that had been transplanted into mice. These antibodies acted as an immunotherapy, activating immune cells and boosting their ability to target and destroy triple negative breast cancer cells expressing FRα.

When FRα-targeting antibodies were linked to cancer growth-inhibiting drugs, they successfully sought out FRα, directly delivering cancer growth-inhibiting drugs to triple negative breast cancer cells, which resulted in smaller, slower-growing tumours.

The team now hope to further develop these novel antibody approaches, with the aim of refining these new lines of attack, and advancing them into clinical trials for triple negative breast cancer patients.

The study is published in Clinical Cancer Research and was funded by leading research charity Breast Cancer Now.

Dr Sophia Karagiannis, Head of Cancer Antibody Discovery and Immunotherapy at King’s College London, said:

Having identified antibodies against this novel target that are able to restrict the growth of triple negative breast cancer cells in the laboratory, we are now concentrating on bringing forth a new generation of more effective antibody therapy approaches. Our ultimate aim is to translate the most promising of these to clinical testing in patients.

Professor Andrew Tutt, Director of the Breast Cancer Now Unit at King’s College London, said:

Through our combined strengths in breast cancer biology, cancer immunology, antibody engineering, and translation of targeted therapies at the Breast Cancer Now Unit at King’s, we are able to venture beyond existing conventional treatments, identify new targets on cancer cells and develop new agents for therapy never before examined in breast cancer. But it’s important to remember that this research is at an early stage and further work is needed in the laboratory before we know if these could develop into treatments for patients.

Dr Simon Vincent, Director of Research at Breast Cancer Now, which funded the study, said:

This is a really important discovery. We hope this new line of attack could now lead to a long-awaited targeted therapy for patients with aggressive ‘triple negative’ breast cancer – for whom treatments are currently very limited.

With triple negative breast cancer still severely lacking in targeted treatments, it remains one of the greatest areas of unmet need in breast cancer. The King's College London Unit is a world-leading centre dedicated to finding new and kinder therapies for this hard-to-treat type of breast cancer – and crucial steps like this are extremely promising.

Priming the immune system to attack tumours is an exciting approach that is now beginning to show promise in breast cancer, and we now hope to see new antibody immunotherapies enter trials for triple negative patients soon. 

The more aggressive breast cancers are, the more likely they are to spread around the body, where they become incurable. It’s vital that we find new ways to stop breast cancer spreading if we are to achieve our ambition that by 2050, everyone who develops breast cancer will live – and live well.

The study was largely funded by Breast Cancer Now – with additional support from Cancer Research UK, the Medical Research Council, the Academy of Medical Sciences, the CR UK/NIHR in England/Department of Health for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre, the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ and King’s College London. Patient tissue samples were provided by King’s Health Partners Cancer Biobank in London.

Breast Cancer Now thanks Walk the Walk and the Sarah Greene Tribute Fund for their very generous support towards Dr Sophia Karagiannis’ work.