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 tumors 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.
"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, 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 tumors fell apart as a result of that assault.
These results provide fresh insight to build new immune therapies for cancer."
To understand what was happening in the tissues of these patients, Vonderheide and Gregory L. Beatty, instructor of Hematology/Oncology, and colleagues turned to a mouse model of pancreatic cancer developed several years ago at Penn.
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," said Vonderheide.
"The tumor is still calling in macrophages, but now we've used the CD40 receptor to re-educate those macrophages to attack - not promote - the tumor."
The researchers believe that the CD40 antibodies also activated T cells in the mice, but the T cells couldn't get into the tumor or its surrounding tissue.
"We learned that T cells have a major problem with migration into tumors, and this may be a particular problem for pancreatic cancer," said Vonderheide.
"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 study has been published in Science.