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Novel immune therapy for pancreatic cancer

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Researchers at the University of Pennsylvania’s Abramson Cancer Center have discovered a novel way of treating pancreatic cancer by activating the immune system to destroy the cancer’s scaffolding. The strategy was tested in a small cohort of patients with advanced pancreatic cancer, several of whose tumours shrank substantially. The team believes their findings – and the novel way in which they uncovered them – could lead to quicker, less expensive cancer drug development.

The authors call the results, published in the 25 March issue of Science, a big surprise. “Until this research, we thought the immune system needed to attack the cancer directly in order to be effective,” said senior author Robert H. Vonderheide, MD, DPhil, an associate professor of Medicine in the division of Hematology/Oncology and the Abramson Family Cancer Research Institute. “Now we know that isn’t necessarily so. Attacking the dense tissues surrounding the cancer is another approach, similar to attacking a brick wall by dissolving the mortar in the wall. Ultimately, the immune system was able to eat away at this tissue surrounding the cancer, and the tumours fell apart as a result of that assault. These results provide fresh insight to build new immune therapies for cancer.”

The current study is part of a unique research model designed to move back and forth between the bench and the bedside, with the investigative team consisting of researchers based in both the laboratory and in the clinic. In the clinical trial led at Penn by Peter O’Dwyer, MD, professor of Hematology/Oncology, and Gregory L. Beatty, MD, PhD, instructor of Hematology/Oncology, pancreatic cancer patients received standard gemcitabine chemotherapy with an experimental antibody manufactured by Pfizer Corporation. The antibody binds and stimulates a cell surface receptor called CD40, which is a key regulator of T-cell activation. The team initially hypothesised that the CD40 antibodies would turn on the T cells and allow them to attack the tumour.

The treatment appeared to work, with some patients’ tumours shrinking substantially and the vast majority of tumours losing metabolic activity after therapy, although all of the responding patients eventually relapsed. When the researchers looked at post-treatment tumour samples, obtained via biopsy or surgical removal, there were no T cells to be seen. Instead, they saw an abundance of another white blood cell known as macrophages.

To understand what was happening in the tissues of these patients, Vonderheide and Beatty and colleagues turned to a mouse model of pancreatic cancer developed several years ago at Penn. Unlike older mouse models that were simplistic models of human disease, new genetically engineered mice develop spontaneous cancers that are very close reproductions of human tumours. “We can perform preclinical trials in these mice with the same principles we use in our patients,” Vonderheide says, noting that the team even used a randomisation protocol to assign individual mice to different arms of the study.

When the investigators treated mice that developed pancreatic cancer with gemcitabine in combination with CD40 antibodies, the results looked like those of the human trial. Some mouse tumours shrank and were found to be loaded with macrophages but contained few or no T cells. Closer inspection showed that the macrophages were attacking what is known as the tumour stroma, the supporting tissue around the tumour. Pancreatic tumours secrete chemical signals that draw macrophages to the tumour site, but if left to their own devices, these macrophages would protect the tumour. However, treating the mice (or patients) with CD40 antibodies seemed to flip that system on its head. “It is something of a Trojan horse approach,” Vonderheide says. “The tumour is still calling in macrophages, but now we’ve used the CD40 receptor to re-educate those macrophages to attack – not promote – the tumour.”

The researchers believe that the CD40 antibodies also activated T cells in the mice, but the T cells couldn’t get into the tumour or its surrounding tissue. “We learned that T cells have a major problem with migration into tumours, and this may be a particular problem for pancreatic cancer,” Vonderheide says. “The area surrounding pancreatic cancers is very dense, fibrotic, and hostile. This is one of the main reasons standard therapies for this disease often work so poorly.”


The researchers are now working on ways to capitalise on their novel information, testing ways to super-charge the macrophage response and to get the T cells into the tumour microenvironment. Vonderheide thinks his team can speed up clinical research by running pilot trials in the mice to test potential therapeutics. Once they understand responses in the mice, then they can use that information to design better human trials.

(Source: University of Pennsylvania: Science)

More information

Cancer
 For more information on cancer, including breast, prostate, kidney and stomach cancer, see Cancer: Overview
.

Immune system
 For more information on the acquired immune system, including about T cells and antibodies, see Acquired Immune System
.


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Dates

Posted On: 6 April, 2011
Modified On: 15 January, 2014

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