Precision drugs could unmask cancers to immune system and boost effects of immunotherapy
Precision cancer drugs called PARP inhibitors have a previously unknown ability to boost the immune system, and could help many more patients benefit from immunotherapy, a new study reveals.
Scientists found that PARP inhibitors sparked a powerful immune response when used against cancer cells with weaknesses in repairing their DNA.
The study changes our understanding of how PARP inhibitors work - and suggests they could be used alongside immunotherapies to boost their effectiveness. Clinical trials have already started to assess this combination.
Some patients have benefited dramatically from a new generation of immunotherapies - but often only between 10 and 20 per cent of patients will respond, with many others' cancers able to hide from the immune system.
Scientists at The Institute of Cancer Research, London, and the Institut Gustave Roussy, France, led by Professor Chris Lord and Dr Sophie Postal-Vinay, found that PARP inhibitors could unmask some of these cancers that can currently evade detection by immune cells.
Their study is published in the Journal of Clinical Investigation and was funded by Breast Cancer Now and Cancer Research UK.
PARP inhibitors such as olaparib block one of the systems which cells use to repair their DNA. They are designed to attack tumours that are already defective at DNA repair, especially ovarian and breast cancers in women with inherited BRCA mutations.
The researchers looked at lung tumours taken from patients, and found those with deficiencies in their DNA repair contained significantly more immune cells within the tumours, compared with tumours in patients with a functioning DNA repair system. This suggested that the DNA repair mutations were stimulating an immune response against the tumours.
They also studied cancer cells from non-small cell lung cancers and triple-negative breast cancers with mutations in DNA repair genes such as ERCC1 or BRCA, to assess whether PARP inhibitors could increase this immune response.
When cancer cells with defective repair systems are treated with PARP inhibitors to block their remaining system of DNA repair, they can no longer repair any DNA damage so accumulate more and more DNA mutations until they die.
The researchers found that the accumulation of DNA damage in cancer cells treated with PARP inhibitors triggered the release of various molecular signals that have the potential to attract immune cells to the tumour, suggesting that treatment with PARP inhibitors could enhance the immune response against these cancer cells.
In one ERCC1-deficient cancer cell line, 24 out of the 50 signalling pathways that were activated after exposure to PARP inhibitors were related to the immune system.
The scientists found that PARP inhibitors could potentially be used to treat lung cancers with faults in their DNA repair genes, in part because of these newly discovered effects on the immune system. By using PARP inhibitors alongside immunotherapy, this immune response could be further enhanced to kill the cancer cells more effectively.
As 30 to 50 per cent of patients with non-small cell lung cancer have a deficiency in the ERCC1 DNA repair system, this could open up a new, more effective ways of treating a large proportion of non-small cell lung cancer patients.
Study leader Professor Chris Lord, Professor of Cancer Genomics at The Institute of Cancer Research, London, said:
"The findings of this study substantially change our understanding of how PARP inhibitors work. We now know that they not only kill tumours by damaging their DNA, but also by attracting immune cells to attack them - acting as a sort of double-pronged attack.
"Immunotherapy is a genuinely brilliant cancer treatment but generally only for the 10 to 20 per cent of people who respond to it. Finding the tumour is half of the battle in immunotherapy so by attracting the immune cells to the tumour, PARP inhibitors could enable the immunotherapy drug to target their attack."
Study co-leader Dr Sophie Postel-Vinay, Clinician Scientist and Medical Oncologist at Gustave Roussy, France, and The Institute of Cancer Research, London, said:
"Our study found that PARP inhibitors enlist immune cells to aid in the killing of cancer cells. This provides a rationale for using PARP inhibitors alongside immunotherapies to further stimulate the immune response to cancer cells with DNA repair defects and enhance the therapeutic benefit of the treatment."
"This will be evaluated in a clinical trial of lung, prostate and bladder cancers, which is starting later this year."
Dr Ian Walker, Director of Clinical Research at Cancer Research UK, said:
"This study highlights the important role that research in the lab plays in helping us devise new clinical trials. Identifying new combinations that make cancer drugs more effective could open up many new treatment options for patients with cancers that are hard-to-treat, like lung cancer. This is an exciting development and we look forward to seeing if PARP inhibitors can improve survival for these patients."
Dr Kotryna Temcinaite, Research Communications Manager at Breast Cancer Now, said:
"These are really promising findings that show once more just how important PARP inhibitors could be in treating a number of cancers. Not only do these drugs interfere with tumour cells' ability to repair DNA but this study suggests they may have additional effects in initiating an immune response, which could then be exploited using other treatments.
"Activating the immune system to attack tumours is an exciting approach that is beginning to show promise in breast cancer. We now look forward to seeing how the combination of PARP inhibitors and checkpoint inhibitors may work in clinical trials for breast cancer patients."
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Notes to editors
For more information please contact Tilly Haynes in the ICR press office on 020 7153 5136 or tilly.haynes@icr.ac.uk. For enquiries out of hours, please call 07595 963 613.
The science underpinning the discovery and development of PARP inhibitors such as olaparib was led by scientists at The Institute of Cancer Research, London. Olaparib is now available on the NHS to treat advanced, chemotherapy-resistant ovarian cancer in women who inherit mutations in one of the BRCA genes.The Institute of Cancer Research, London, is one of the world's most influential cancer research organisations.
Scientists and clinicians at The Institute of Cancer Research (ICR) are working every day to make a real impact on cancer patients' lives. Through its unique partnership with The Royal Marsden NHS Foundation Trust and 'bench-to-bedside' approach, the ICR is able to create and deliver results in a way that other institutions cannot. Together the two organisations are rated in the top four centres for cancer research and treatment globally.
The ICR has an outstanding record of achievement dating back more than 100 years. It provided the first convincing evidence that DNA damage is the basic cause of cancer, laying the foundation for the now universally accepted idea that cancer is a genetic disease. Today it is a world leader at identifying cancer-related genes and discovering new targeted drugs for personalised cancer treatment.
A college of the University of London, the ICR is the UK's top-ranked academic institution for research quality, and provides postgraduate higher education of international distinction. It has charitable status and relies on support from partner organisations, charities and the general public.
The ICR's mission is to make the discoveries that defeat cancer. For more information visit http://www.icr.ac.uk
About Gustave Roussy:
Gustave Roussy, Europe's leading comprehensive cancer centre, is a global, patient-focused centre of excellence. It brings together 3,100 professionals dedicated to treatment, research and teaching. Each year, more than 48,000 patients of whom 11,400 were attending their first appointment are seen in outpatients. 28% of patients treated in 2017 were included in clinical research studies.
For further information, visit https://www.gustaveroussy.fr/en
About Cancer Research UK:
Cancer Research UK is the world's leading cancer charity dedicated to saving lives through research. Cancer Research UK's pioneering work into the prevention, diagnosis and treatment of cancer has helped save millions of lives. Cancer Research UK receives no funding from the UK government for its life-saving research. Every step it makes towards beating cancer relies on vital donations from the public. Cancer Research UK has been at the heart of the progress that has already seen survival in the UK double in the last 40 years. Today, 2 in 4 people survive their cancer for at least 10 years. Cancer Research UK's ambition is to accelerate progress so that by 2034, 3 in 4 people will survive their cancer for at least 10 years. Cancer Research UK supports research into all aspects of cancer through the work of over 4,000 scientists, doctors and nurses. Together with its partners and supporters, Cancer Research UK's vision is to bring forward the day when all cancers are cured.About Breast Cancer Now:
Breast Cancer Now is the UK's largest breast cancer charity. Breast Cancer Now's ambition is that by 2050 everyone who develops breast cancer will live - and live well. The charity is determined to stop women dying from the disease, working in a new, collaborative way and bringing together all those affected by the disease to fund research, share knowledge and find answers. Breast Cancer Now's world-class research is focused entirely on breast cancer. The charity supports nearly 380 of the world's brightest researchers at 31 locations across the UK and Ireland. Together, they're working to discover how to prevent breast cancer, how to detect it earlier and how to treat it effectively at every stage so we can stop the disease taking lives. Breast cancer is still the most common cancer in the UK. Nearly 700,000 people living in the UK have experienced a diagnosis and one in eight women will face it in their lifetime. This year alone, around 55,000 women and 350 men will be told they have the disease. The UK still has one of the lowest breast cancer survival rates in Western Europe and this year alone around 11,500 women will lose their lives. It's time to act. Breast Cancer Now launched in June 2015, created by the merger of leading research charities Breast Cancer Campaign and Breakthrough Breast Cancer. For more information on Breast Cancer Now's work, visit breastcancernow.org or follow us on Twitter or on Facebook.The National Institute for Health Research (NIHR): improving the health and wealth of the nation through research. Established by the Department of Health and Social Care, the NIHR:
funds high quality research to improve health trains and supports health researchers provides world-class research facilities works with the life sciences industry and charities to benefit all involves patients and the public at every stepFor further information, visit the NIHR website (http://www.nihr.ac.uk).