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Penn researchers uncover novel immune therapy for pancreatic cancer
Date:3/24/2011

es would turn on the T cells and allow them to attack the tumor.

The treatment appeared to work, with some patients' tumors shrinking substantially and the vast majority of tumors losing metabolic activity after therapy, although all of the responding patients eventually relapsed. When the researchers looked at post-treatment tumor 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 tumors. "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 randomization 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 tumors 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 tumor stroma, the supporting tissue around the tumor. Pancreatic tumors secrete chemical signals that draw macrophages to the tumor site, but if left to their own devices, these macrophages would protect the tumor. 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 tumor is still calling in macrophages, but now we've used the CD40 receptor to re-educate those macrophages to attack not promote
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Contact: Holly Auer
holly.auer@uphs.upenn.edu
215-200-2313
University of Pennsylvania School of Medicine
Source:Eurekalert

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