Researchers at the Johns Hopkins Kimmel Cancer Center have developed and tested a vaccine that triggered the growth of immune cell nodules within pancreatic tumors, essentially reprogramming these intractable cancers and potentially making them vulnerable to immune-based therapies.
In their study described in the June 18 issue of Cancer Immunology Research, the Johns Hopkins team tested the vaccine in 39 people with pancreatic ductal adenocarcinomas (PDAC), the most common form of pancreatic cancer. The disease becomes resistant to standard chemotherapies and is particularly lethal, with fewer than 5 percent of patients surviving five years after their diagnosis.
PDACs do not typically trigger an immune response against the cancer cells that comprise, but with the help of a vaccine developed by Johns Hopkins researcher Elizabeth Jaffee, M.D., the scientists were able to "reprogram" tumors to include cancer-fighting immune system T cells.
The vaccine, known as GVAX, consists of irradiated tumor cells that have been modified to recruit immune cells to a patient's tumor. The researchers tested GVAX in combination with an immune modulator drug called cyclophosphamide, which targets a type of immune cell, called Tregs, that typically suppresses the immune response of certain T cells that destroy cancer.
The reprogramming is designed to make the tumors more vulnerable to other immune-modulating drugs that have been useful in fighting other cancers, said Jaffee, The Dana and Albert "Cubby" Broccoli Professor of Oncology at the Johns Hopkins University School of Medicine.
Jaffee and colleague, Lei Zheng, M.D., say the vaccine could potentially convert many types of tumors to a state where immunotherapies can have a much larger impact.
For example, Jaffee says, in certain melanomas, "we've tested immunotherapies that target T cells and have found a 10-30 percent response in cancers that naturally have the ability to trigger immune system responses, but there are few options for the other 70 percent of patients who barely or never respond to immunotherapies."
The researchers found that the vaccine created structures called tertiary lymphoid aggregates within the patients' tumor, structures that help regulate immune cell activation and movement. The aggregates, which appeared in 33 of the 39 patients treated with the vaccine, had surprisingly well-organized structures that do not typically appear in these types of tumors naturally, said Zheng, an assistant professor of oncology and surgery at the Johns Hopkins University School of Medicine. "This suggests that there has been significant reprogramming of lymphocyte structures within the tumor."
The aggregates could "really shift the immunologic balance within a tumor, setting up an environment to activate good T cells to fight the cancer, by tamping down Tregs," Jaffee said, "and such T cells would be educated to recognize the cancer proteins in that specific tumor environment."
The vaccine and the resulting lymphoid aggregates boosted the activity of several molecular mechanisms that, like Tregs, inhibit cancer-fighting immune cells. That may sound like a bad thing, but it actually provides many new potential targets within the tumor for immune-modulating drugs, Zheng explained.
The researchers' next study in PDAC patients will test a combination of GVAX and an antibody to PD-1, one of the immune-suppressing molecules that became more active after vaccination. "We think combinations of immune therapies will have the biggest impact," he says.
Other Hopkins researchers involved in the study include Eric R. Lutz, Annie A. Wu, Elaine Bigelow, Rajni Sharma, Guanglan Mo, Kevin Soares, Sara Solt, Alvin Dorman, Anthony Wamwea, Allison Yager, Daniel Laheru, Christopher L. Wolfgang, Ralph H. Hruban, and Robert Anders. Jiang Wang at the University of Cincinnati College of Medicine was also a co-author on the study. Jaffee is co-director of the Skip Viragh Pancreas Cancer Clinical Care and Research Center at Johns Hopkins.
The study was supported by the National Institutes of Health's National Cancer Institute (K23 CA148964-01, P50 CA062924), the Johns Hopkins School of Medicine Clinical Science Award, the American Society of Clinical Oncology Young Investigator Award, the Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins, The National Pancreas Foundation, the Lefkofsky Family Foundation, the Lustgarten Foundation, and the Sol Goldman Pancreatic Cancer Center.
Under a licensing agreement between Aduro BioTech Inc. and the Johns Hopkins University and Jaffee, the University is entitled to milestone payments and royalty on sales of the vaccine product.