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Understanding how an individual survives cancer, and why they respond well to therapy, can be vital in identifying new therapeutic targets. A new project seeks to see why some advanced pancreatic cancer patients overcome the odds and respond positively to treatment.

Patient talking to a nurse in a clinic

Pancreatic cancer is the most lethal of the common cancers. The 5-year survival rate is 9%, dropping to less than 1% if it has metastasised and spread to other parts of the body. The only hope of cure is to treat early disease by surgical removal. In these cases, survival can rise to around 40%.

However in most patients, the disease is too advanced for surgery at the time of diagnosis and treatment is limited to chemotherapy, which at best prolongs life by a few months. In spite of this poor prognosis, there are at times very rare cases of patients with advanced stage 4 pancreatic cancer, who receive treatment and eventually go into remission. But, why have these individuals responded so well? Was it due to the individual’s genetic makeup, immune system or their unique pancreas?

The idea that the immune response was an important factor in these exceptional survivors, became an area of interest to the Kennedy Institute-based researchers Prof. Kim Midwood and Prof. Patrick Venables. Funded by Continuum Life Sciences, an organisation founded by Dr James Hull, this team recruited lead scientist Dr Anja Schwenzer to analyse samples collected from patients with pancreatic cancer, with a view to documenting the immune responses to the tumour, and its relationship with survival rates.

They analysed three groups of patients with advanced cancer: short-term survivors (typically less than 6 months), medium term (1-2 years) and exceptional long-term survivors (still alive after 5 years in spite of metastatic disease). For the short and medium term survivors, they used historical blood samples from the landmark SCALOP study run by Oxford-based principle investigators Profs Somnath Mukherjee and Eric O'Neill.

For the exceptional long term survivors, they looked at blood from volunteers who have survived stage 4 pancreatic cancer donated to Continuum Life Sciences. By analysing immune responses in the survivors, they have identified targets on their pancreatic tumours that are used in a protective immune response.

The team now plan to isolate antibodies from the exceptional survivors, clone them in the lab, and use these monoclonal antibodies, to treat pancreatic cancer patients otherwise destined to die of the disease. These antibodies will be cloned from Continuum patients, in collaboration with Prof Gavin Screaton who has pioneered the use of patient-derived monoclonal antibodies to treat viral infections. This will be one of the first attempts to exploit monoclonal antibody treatment, which is of proven use in viruses, and extend it to treat pancreatic cancer.

Pancreatic cancer is often described as an “immune desert” and the “toughest nut to crack” in the field of immunotherapy in cancer. Monoclonal antibodies are the most important advance in cancer therapy in the last 20 years. In particular, the Nobel prize-winning monoclonal antibodies known as checkpoint inhibitors have transformed the prospects of patients with many cancers, malignant melanoma being a prime example.

Unfortunately, checkpoint inhibitors have no benefit in pancreatic cancer. The Oxford group of investigators and Continuum believe that patients who survive metastatic pancreatic cancer are the “extreme phenotypes” who demonstrate that even the most lethal disease can be controlled by an appropriate immune response.

Making patient-derived monoclonal antibodies from them is exploiting this immune response for the benefit of others. Antibodies have an anti-tumour effect in their own right, but perhaps more importantly, direct other arms of the immune response, such as T cells and natural killer cells to target and attack the tumour. Because monoclonal antibodies are already widely used in clinical practice, this approach provides an opportunity to translate an experimental approach into a medicine to crack the toughest nut of all: pancreatic cancer.

About this study

Prof Patrick J Venables is head of the Citrullination and Inflammation group at the Kennedy Institute of Rheumatology, University of Oxford. He is also a survivor of the most malignant form of pancreatic cancer, stage 4 poorly differentiated adenocarcinoma of the pancreas, treated with chemotherapy and surgery in 2011-2012. Professor Venables will be one of the first donors for therapeutic patient-derived monoclonal antibodies

Prof Kim Midwood is a Professor of Matrix Biology at the Kennedy Institute of Rheumatology. On top of the establishment of Matrix Immunology groups in Oxford and Imperial College London, she founded the BioTech company Nascient Ltd, which has developed monoclonal antibodies that have applications in benefiting patients with autoimmune disease, as well as hard to treat cancers. Her research focuses on how changes in the extracellular matrix affect cellular signalling pathways in inflammatory diseases including arthritis, fibrosis and cancer, as well as identifying novel therapeutic targets in the ECM.

Dr Anja Schwenzer is a post-doctoral research scientist who has pioneered work with Profs Venables and Midwood on autoimmunity in rheumatoid arthritis, elements of which are similar to the immune response in pancreatic cancer.

This work is being funded by Continuum Life Sciences: an organisation founded by Dr James Hull, who is also an exceptional cancer survivor. The group comprises 6 universities, including Oxford, whose aim is to find novel treatments through research into long-term cancer survivors

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