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A new vaccine triggered the growth of immune cell nodules within pancreatic tumors, reprogramming these intractable cancers and making them vulnerable to immune-based therapies.
Pancreatic ductal adenocarcinomas (PDACs) are the most common form of pancreatic cancer. This type of pancreatic cancer becomes resistant to standard chemotherapies and is especially lethal. Fewer than 5% of patients survive 5 years after their diagnosis.
Typically, PDACs do not trigger an immune response against the cancer cells of the tumor because the microenvironment of the tumor provides a significant barrier to immune cell infiltration and function. With the help of the new vaccine, the tumors were reprogrammed to include cancer-fighting T cells.
The vaccine, known as GVAX, consists of irradiated tumor cells modified to recruit immune cells to a patient's tumor. The researchers tested GVAX alone and in combination with the immune modulator drug cyclophosphamide to study how immunotherapy altered the tumor microenvironment. Cyclophosphamide targets regulatory T cells (Tregs) that suppress the immune response of T cells that destroy cancer.
The reprogramming made the tumors more vulnerable to immune-modulating drugs that have been useful in fighting other cancers, said Elizabeth Jaffee, MD, professor of oncology at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
Jaffee and colleague, Lei Zheng, MD, said the vaccine has the potential to change many types of tumors, allowing immunotherapies to play a larger role in cancer treatment.
In certain melanomas, "we've tested immunotherapies that target T cells and have found a 10% to 30% response in cancers that have the natural ability to trigger immune system responses. There are few options for the other 70% of patients who have little or no response to immunotherapies,” Jaffee said.
The GVAX vaccine created structures called tertiary lymphoid aggregates within the tumors, which regulate immune cell activation and movement. The tertiary lymphoid aggregates occurred in 33 of the 39 patients who received the vaccine and were surprisingly well-organized.
“These structures do not appear in this type of tumor naturally. This suggests that there has been significant reprogramming of lymphocyte structures within the tumor," said Zheng, assistant professor at the Johns Hopkins University School of Medicine.
The aggregates could “shift the immunologic balance within a tumor, setting up an environment to activate good T cells to fight the cancer, by tamping down Tregs. These T cells would be educated to recognize the cancer proteins in that specific tumor environment,” said Jaffee.
The vaccine and the resulting lymphoid aggregates boosted the activity of several molecular mechanisms that inhibit cancer-fighting immune cells. That provides many potential targets within the tumor for immune-modulating drugs, said Zheng.
This study was published in Cancer Immunology Research (2014; doi:10.1158/2326-6066.CIR-14-0027).