Researchers from the Johns Hopkins University School of Medicine in Baltimore, MD, have discovered that a combination of a vaccine and low-dose chemotherapy may make pancreatic cancer susceptible to the effects of immunotherapy. These findings are significant because, typically, these cancers do not respond to immunotherapy, with fewer than 5% of patients surviving 5 years after diagnosis.
"Pancreatic cancer is one of a number of malignancies that typically lack tumor-infiltrating effector lymphocytes and have been considered 'nonimmunogenic' neoplasms," says Dr. Lei Zehng, assistant professor of oncology and surgery at the Sidney Kimmel Comprehensive Cancer Center and the Skip Viragh Center for Pancreatic Cancer Research and Clinical Care at Johns Hopkins.
"The only curative treatment for pancreatic cancer," Dr. Zehng explains, "is complete surgical resection, and approximately 80% of patients who undergo surgery relapse and die from the disease within 5 years, suggesting a need for effective strategies."
The new study from Dr. Zheng's team - published in Cancer Immunology Research - was intended to evaluate how patients with pancreatic ductal adenocarcinomas (PDAC) might respond to a new vaccine.
The vaccine, called GVAX, was developed by Johns Hopkins researcher Dr. Elizabeth Jaffee to "reprogram" tumors to include immune system T cells that are able to fight cancer. To accomplish this, GVAX is made of irradiated tumor cells that have been modified to recruit immune cells to the patient's tumor.
Dr. Jaffee says that the vaccine has the potential to convert many different types of tumors to a state where they are susceptible to immunotherapies. These include immune-modulating chemotherapy drugs such as cyclophosphamide, which targets "tregs" - a type of immune cell that suppresses the immune responses of the cancer-fighting T cells.
The team recruited 59 patients with PDAC for their study, which ran from 2008-2012. One group of patients received GVAX on its own, another group of patients received the vaccine plus 200 mg/m2 of cyclophosphamide, and another received the vaccine plus 100 mg oral doses of cyclophosphamide (daily, on alternate weeks).
Vaccine 'created lymphoid aggregates' that regulate immune cell activation
All patients underwent surgery to remove their tumors 2 weeks after receiving the vaccination. The researchers discovered from analyzing the excised tumors that the vaccine had caused the creation of structures called "tertiary lymphoid aggregates."
Analyzing the tumors, the researchers discovered that the vaccine had caused the creation of structures called "tertiary lymphoid aggregates."
These aggregates - which formed in 33 of the 39 patients who remained disease free - were found to help regulate immune cell activation and movement, and they do not appear in these types of tumor naturally.
"This suggests that there has been significant reprogramming of lymphocyte structures within the tumor," concludes Dr. Zheng.
Dr. Jaffee says that these aggregates could "really shift the immunologic balance within a tumor, setting up an environment to activate good T cells to fight the cancer," adding that "such T cells would be educated to recognize the cancer proteins in that specific tumor environment."
Looking more closely, the researchers also found that the tumors had become immunogenic, which means the immune cells surrounding the tumor now had the ability to attack the cancer cells.
The tumors had become immunogenic because the ratio of "effector T cells" to "regulatory T cells" had increased. The researchers observed that the greater the ratio of effector to regulatory T cells found in a patient, the better that patient's chances of survival were.
"Our study has suggested a new model for developing more effective immunotherapy for traditionally nonimmunogenic tumors like pancreatic cancer," Dr. Zheng says. "We will next investigate immunotherapies that include both cancer vaccines and treatments that boost the 'good' immune-regulatory signals or block the 'bad' immune-regulatory signals."