Priming Pancreatic Cancer Cells With a Vaccine May Allow Them to Respond to Immunotherapy
Pancreatic ductal adenocarcinoma is considered a “nonimmunogenic” neoplasm and does not typically respond to immunotherapy, in part due to a complex tumor microenvironment that provides a formidable barrier to immune infiltration and function. A new study by Lutz et al has found that by priming the pancreatic ductal adenocarcinoma cells with GVAX Pancreas—a vaccine made from allogeneic pancreatic cancer cells that have been genetically modified to produce granulocyte macrophage colony-stimulating factor—and low-dose cyclophosphamide prior to surgery, it converted pancreatic ductal adenocarcinoma cells into immunogenic cancers that may respond to immunotherapy, such as PD-1 inhibitors. The study is published in Cancer Immunology Research.
Study Method
Between 2008 and 2012, the researchers enrolled 59 patients with pancreatic ductal adenocarcinoma into this study and randomly assigned them among three arms: Patients in arm “A” received GVAX alone, patients in arm “B” received GVAX plus a single intravenous dose of cyclophosphamide at 200 mg/m2, and patients in arm “C” received GVAX plus 100-mg oral doses of cyclophosphamide once daily, on alternate weeks.
About 2 weeks after the treatment, all patients underwent surgery to remove their pancreatic tumors. Fifty-four patients successfully underwent the Whipple procedure and received the second GVAX treatment. Five patients were found to have liver metastases during surgery and underwent bypass surgery. Of the 59 patients, 39 remained free of disease after surgery and received standard adjuvant chemotherapy and radiotherapy. Patients remaining disease-free following chemoradiotherapy received up to four additional GVAX treatments every 4 weeks, and their tumors were then analyzed.
Study Findings
For comparative analysis, in addition to tumor samples from the 39 patients, the researchers used tumor samples from 58 patients from other studies. Four were unvaccinated patients and 54 were patients whose tumor samples were collected prior to vaccination.
The researchers found that the vaccine-chemotherapy combination resulted in the formation of lymphoid aggregates within the tumors in 33 of the 39 patients within 2 weeks of vaccination.
Immunohistochemical analysis of the various immune cell types found in the tumors after vaccination showed an increase in the ratio of effector T cells to regulatory T cells, which meant that the tumors had become immunogenic and the immune cells in the tumor area were capable of fighting the cancer cells. An increase in the ratio was associated with better survival.
The researchers also found that the tumors from patients who survived for more than 3 years after the vaccine therapy had enhanced signaling pathways that promoted immune responses, compared with those who survived for less than 1.5 years following vaccination.
Possible Additional Key Targets
“We are further dissecting the immune signatures within the lymphoid aggregates to study the TGF-beta and Th17 signaling pathways,” said Lei Zheng, MD, PhD, a coauthor of the study, and 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 the Johns Hopkins University School of Medicine in Baltimore, in a statement. “TGF-beta and Th17 pathways may also be key targets, in addition to PD-1/PD-L1, for treatments that enhance vaccine-induced antitumor immune responses in pancreatic cancer.”
“On the basis of our findings, we propose a new model in which traditionally ‘nonimmunogenic’ tumors can be converted into ‘immunogenic’ tumors responsive to combination immune-based therapies,” concluded the study authors. “Our model provides the strongest rationale so far for combining immune-modulating agents with vaccination in patients whose tumors do not naturally contain abundant effector T cells.”
Dr. Zheng declared no conflicts of interest. Under a licensing agreement between Aduro BioTech, Inc, and the Johns Hopkins University and E.M. Jaffee, the University is entitled to milestone payments and royalty on sales of the vaccine product described in this article.
This study was funded by the National Institutes of Health, the Johns Hopkins School of Medicine Clinical Scientist 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, the Sol Goldman Pancreatic Cancer Center, and the AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research Award.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
