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New Effective Treatment For Deadly Pancreatic Cancer May Be On Its Way

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Pancreatic Cancer Immune Map Provides Clues For Precision Treatment Targeting

Pancreatic cancer patients may benefit from future precision treatments as a new study shows how some tumours may potentially be more susceptible to macrophage-based therapies.

The study which is published in Nature Communications was led by Associate Professor Shivan Sivakumar from the University of Birmingham and Associate Professor Rachael Bashford-Rogers at the University of Oxford and provides the most detailed immune map for pancreatic cancer. The findings suggest that some tumour cells are more likely to be infiltrated by T cell treatments, while others had myeloid cell infiltration. This means that cells such as macrophages could be suitable for future immunotherapeutic treatments in some cases.

Using cells from twelve patients, the research team created a single cell map of tumour infiltrating immune cells and peripheral immune cells, coupled with gene expression, single cell TCR and BCR sequencing and identifying proteins expressed on these cells. The team then verified their findings using two other large publicly available pancreatic cancer datasets.

Dr Shivan Sivakumar, Associate Professor of Oncology from the University of Birmingham and lead author of the study said:

"Pancreatic cancer is a tumour that does not respond to existing immunotherapies (checkpoint inhibitors). A basis for this is that there is not the same immunogenic reaction to the tumour that exists in other cancers. We therefore mapped out how the immune system is constructed in pancreatic cancer patients. This has helped us understand with a high degree of confidence what immune cells are present in pancreatic cancer and let us see how the tumour evades the immune system.

"We demonstrate the need for trials to assess changes in immune infiltration over time. Collectively our data provides a foundation for understanding the failure of immunotherapy in pancreatic cancer with an avenue for designing novel therapeutics and tailored interventions.

Rachael Bashford-Rogers, Associate Professor of Molecular and Cellular Biochemistry from the University of Oxford and a senior author of the study said:

"We have uncovered distinct immune environments in pancreatic cancer, revealing new therapeutic opportunities to improve outcomes for this deadly disease. By leveraging single-cell multi-omics and novel computational approaches, this study identifies potential strategies such as boosting certain cell responses, and depleting suppressive immune cells to enhance immune-based treatments."

Potential therapeutic targets identified

The study has also uncovered the important understanding about the role of specific immune cells, such as activated regulatory T cells (Tregs) and B cells, in the immunopathology of this disease. The team have found that these cells could help to distinguish patients that may benefit from targeted treatments that activate the existing immune response in the tumour area (rich in B and T cells) versus those that have a highly suppressive tumour environment (rich in myeloid cells). Tackling these cells would play an important therapeutic strategy in the future against this disease.

With this understanding, potential targets have been identified with more weight being given to the target TIGIT that was previously identified as a target of interest in this disease and now this work also suggests that CD47 can be targeted too. The work also suggests strategies to boost B cell responses, target immunosuppressive macrophages and deplete activated intratumoural Tregs will be of benefit to different subsets of patients, and these are now fertile areas to investigate.

Pancreatic cancer is among the deadliest cancers globally, with a survival rate beyond 10 years of less than 1% in England (2013-2017). It is often only when the cancer has reached an advanced stage that physical symptoms appear, at which point it becomes more difficult to treat.

Dr Sivakumar said:

"As an honorary consultant in medical oncology focused on pancreatic, liver and biliary tract cancers, I am perhaps more familiar than most with the devastating nature of this disease. According to the charity Pancreatic Cancer UK, it is the 5th biggest cancer killer in the UK, with 9,000 deaths every year. Pancreatic cancer also has the lowest survival rates of all common cancers, with a five-year survival rate of less than 7%.

"Sadly, pancreatic cancer is typically diagnosed at a late stage, when curative surgery is no longer an option. The problem is exacerbated by the fact that for the 'lucky' 1 in 10 who are eligible for surgery, the recurrence rate of pancreatic cancer after surgical treatment is over 80%.

"We are currently running the mRNA vaccine study for pancreatic cancer to see if this can prevent recurrence in Birmingham and have two further studies imminently opening in this disease.. Working closely with the private sector who play a key role in drug development, and armed with the insights we have gained from this study and others, we are now also constructing our own investigator initiated studies to help see if we can use precision immunotherapeutics to help provide good treatment options for these patients.

"Any potential breakthroughs in pancreatic cancer treatment are therefore so important. With over 150 pancreatic cancer operations happening each year here in Birmingham, it's a fantastic place to do translational research that will ultimately impact on patient care and outcomes."

Most Pancreatic Cancer Isn't Caught Until It's Late Stage — A New Blood Test Could Change That

Get pumped!

Scientists from Oregon Health & Science University have developed a blood test called PAC-MANN that is said to be less invasive, cheaper and more robust than traditional screening methods for pancreatic cancer, potentially leading to more treatment options and better outcomes.

"The problem with pancreatic cancer is that we often catch it too late," said Jared Fischer, a scientist with OHSU Knight Cancer Institute's Cancer Early Detection Advanced Research Center (CEDAR).

"Our goal with PAC-MANN is to give clinicians a tool that can detect the disease much earlier, when more treatment options are available and there is a better chance of survival," Fischer added.

Scientists have developed a blood test called PAC-MANN that is said to be less invasive, cheaper and more robust than traditional screening methods for pancreatic cancer. OHSU/Christine Torres Hicks What is pancreatic cancer? The pancreas, a gland situated behind the stomach, produces digestive enzymes that break down food and secretes hormones like insulin to regulate blood sugar. Pancreatic cancer is illustrated here with the tumors in red. Matthieu – stock.Adobe.Com

The pancreas, a gland situated behind the stomach, produces digestive enzymes that break down food and secretes hormones like insulin to regulate blood sugar.

The exact cause of pancreatic cancer is unknown, but some genetic syndromes, smoking, obesity, diabetes, chronic pancreatitis and excessive alcohol use can raise your risk.

Pancreatic cancer is often discovered in advanced stages because it doesn't usually cause symptoms until it has spread to other organs, limiting treatment options.

The American Cancer Society estimates that 67,400 Americans will be diagnosed with pancreatic cancer this year and nearly 52,000 will die from the disease.

How could PAC-MANN help? Metastatic pancreatic ductal adenocarcinoma, the most common and deadly form of pancreatic cancer, is seen here. Getty Images/iStockphoto

PAC-MANN was created using blood samples from 350 patients who had pancreatic cancer, were at high risk for it or were controls.

The research team looked for proteins in the blood called proteases that become more active in people with the most common and deadly form of pancreatic cancer.

PAC-MANN was able to discern patients with pancreatic cancer from healthy patients and those with non-cancerous pancreatic issues 98% of the time.

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It also helped detect early-stage cancer with 85% accuracy when used with a CA 19-9 blood test. Turnaround time for that test, which measures the level of the protein cancer antigen 19-9, is typically one to two days.

"The big difference with [PAC-MANN] is the cost: It takes only 8 microliters of blood and 45 minutes to run the test at a cost of less than a penny per sample," said Jose L. Montoya Mira, a research engineer at OHSU's CEDAR and the study's lead author. "This could easily be used in rural and underserved settings, where traditional tests are not or cannot be used."

PAC-MANN could also track how well treatments were working and guide therapeutic decisions.

What's next? Cancer researchers Jared Fischer (left) and Jose Luis Montoya Mira, who developed PAC-MANN, will continue testing their method. OHSU/Christine Torres Hicks

The results of the study were published this week in the journal Science Translational Medicine.

Montoya and Fischer have plans for more trials, including one involving patients at high risk of developing pancreatic cancer.

"Hopefully," Fischer said, "this is one step toward ending cancer as we know it."

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