April 16, 2011 by staff
Pancreatic Cancer, Researchers at the University of Pennsylvania, Abramson Cancer Center have discovered a new way of treating pancreatic cancer by activating the immune system to destroy cancer scaffolds. The strategy has been tested in a small cohort of patients with advanced pancreatic cancer, several of whose tumors were substantially reduced. The team believes that its results – and the new way they uncovered – could lead to faster development of less expensive cancer drugs.
The authors call the results, published in the March 25 Science, a big surprise. “Until this research, we believe that the immune system needs to attack the cancer directly in order to be effective,” said lead author Robert H. Vonderheiden, MD, DPhil, associate professor of medicine in the Division of Hematology / Oncology and the Abramson Family Cancer Research Institute. “We now know that is not necessarily so. Attacking the dense tissue surrounding the cancer is another approach, similar to an attack on a brick wall, dissolving the mortar on the wall? Ultimately, the immune system was able to eat away in the cancer and surrounding tissue tumors collapsed as a result of that assault. These results provide a new perspective on the construction of new immune therapies against cancer. ”
The current study is part of a unique research model designed to move back and forth between the bank and night, with the research team consisting of researchers based in the laboratory and clinic. In a clinical trial led by Penn Peter O’Dwyer, MD, professor of Hematology / Oncology, and Gregory L. Beatty, MD, PhD, professor of Hematology / Oncology, patients with pancreatic cancer received standard chemotherapy with gemcitabine with an experimental antibody manufactured by Pfizer Corporation. The antibody binds to and stimulates a cell surface receptor called CD40, which is a key regulator of T cell activation The team initially hypothesized that CD40 antibodies in turn T cells and allow them to attack the tumor.
The treatment seemed to work, some patients with tumors of the substantial reduction and the vast majority of tumors lose metabolic activity after therapy, although all responding patients eventually relapse. When the researchersanlyzed tumor samples after treatment, obtained by biopsy or surgical removal, there were no T cells remains to be seen. Instead, they saw a lot of other white blood cells known as macrophages.
To understand what was happening in the tissues of these patients, Vonderheiden and Beatty and colleagues turned to a mouse model of pancreatic cancer developed several years ago at Penn. Unlike the old mouse models were simplistic models of human disease, new genetically modified mice that develop spontaneous cancers are very close replicas of human tumors. “We can perform the preclinical studies in mice with the same principles we use in our patients,” says Vonderheiden, noting that the team even used a randomized protocol to assign individual mice for the different branches of study.
When the researchers treated mice that developed pancreatic cancer with gemcitabine in combination with CD40 antibodies, the results looked like the human trial. Some tumors in mice was reduced and found to carry the macrophages, but little or no T-cell content Closer inspection revealed that the macrophages are attacking what is known as the tumor stroma, the supporting tissue around the tumor. Pancreatic tumors secrete chemical signals that attract macrophages to the tumor site, but if left to their fate, these macrophages may protect against cancer. However, treatment of mice (or patients) with CD40 antibodies seemed to turn the system on its head. “It’s something like a Trojan horse approach,” says Vonderheiden. “The tumor is still calling on macrophages, but now we have used the CD40 receptor of macrophages to re-educate the attacks – not to promote tumor -.”
Researchers believe that CD40 antibodies also activated T cells in mice, but T cells could not enter the tumor or its surrounding tissues. “We have learned that T cells have a serious problem of migration in tumors, and this may be a particular problem for pancreatic cancer,” says Vonderheiden. “The area surrounding the pancreatic cancer is very dense, fibrous, and hostile. This is one of the main reasons why standard therapies for this disease often work so badly.”
The researchers are now working on ways to take advantage of novel information, testing ways to super-charge the response of macrophages and for T cells in the tumor microenvironment. Vonderheiden believes his side can accelerate clinical research through the implementation of pilot tests in mice to test potential therapies. Once they understand the responses in mice, then you can use that information to improve the design of human trials.
[Source: image via MESOTHELIOMAZ.INFO]
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