Long-term treatment of pancreatic cancer using the chemotherapy drug gemcitabine leads to extensive reprogramming of the immune microenvironment, sensitizing tumors to the benefit of a multi-drug immunotherapy regimen, according to new research from the University of Illinois College of Medicine.
Pancreatic ductal adenocarcinoma (PDAC) – the most common form of pancreatic cancer – is projected to be the second leading cause of cancer-related death in the United States, with an overall five-year survival rate of less than 9%. Patients are often diagnosed in late clinical stages and are seldom eligible for surgery, since the disease has already spread throughout the body. As a result, most cases are predominantly managed through chemotherapy, which improves survival, though nearly all tumors have or will develop some degree of drug resistance. Therefore, median survival remains low – six to 12 months.
“Immunotherapy has revolutionized cancer treatment in the last decade, and strategies to re-activate anti-tumor immunity are now standard of care in several malignancies,” said Ajay Rana, PhD, Endowed Professor and Director of Research in the Department of Surgery at the University of Illinois College of Medicine and co-leader of the UI Cancer Center’s Translational Oncology Program. “Despite the rapid progress for immunotherapy in most solid cancers, progress for immunotherapy in PDAC has been exceptionally difficult.
“Pancreatic tumors are poorly immunogenic, with diminished antigen presentation and a highly immunosuppressive tumor microenvironment. As a result, immunotherapies such as immune checkpoint inhibitors have yet to show clear efficacy in the treatment of pancreatic cancer.”
The study has been published in the journal Cancer Research.
Gemcitabine, a chemotherapy agent first approved by the Food and Drug Administration for pancreatic cancer in 1996, is now used in combination with albumin-conjugated (nab) paclitaxel as a first-line treatment option for metastatic PDAC, Rana said. Gemcitabine-based chemotherapy was considered the only effective treatment for PDAC patients until 2013, when the FDA approved the multidrug FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) regimen, which is also widely used in treating metastatic PDAC. The treatment approach shows “superior efficacy but has a high rate of serious adverse effects,” Rana said.
“While both regimens offer a modest survival benefit to the majority of patients, nearly all will eventually progress on treatment,” he said. “With no FDA-approved third-line medications, patients who progress on these treatments are eventually provided only symptomatic or hospice care. As such, there is an urgent clinical need to identify novel therapeutic approaches for patients in the second- or third-line setting.”
To identify an effective treatment strategy for patients who have exhausted all current treatment options, Rana, along with Daniel Principe, a MD/PhD student at the University of Illinois at Chicago, explored how long-term care with gemcitabine alters the PDAC tumor microenvironment. Using a combination of transgenic mouse models, primary cell line-derived xenografts and established cell lines, they discovered that long-term treatment with gemcitabine-based chemotherapy enhances the presentation of tumor antigen, thereby allowing tumor cells to become more easily recognized by cytotoxic T-cells.
Through these experiments, Rana’s laboratory also discovered that long-term treatment with gemcitabine-based chemotherapy increases the expression of negative immune checkpoints such as PD-L1, a protein that inhibits the effector function of cytotoxic T-cells by binding its receptor (PD-1). Gemcitabine treatment also enhanced the biosynthesis of the soluble immunosuppressant transforming growth factor beta (TGFβ), which cooperates with PD-L1 to help tumor cells escape immune surveillance despite the increased presentation of self-antigen.
“Combining gemcitabine and anti-PD-1 treatment in genetically modified mouse models of PDAC failed to alter the course of the disease unless the mice also underwent genetic or pharmacologic ablation of TGFβ signaling,” Principe said. “In the setting of TGFβ signaling deficiency, gemcitabine and anti-PD-1 led to a robust anti-tumor immune response, with a corresponding decrease in tumor burden, which markedly enhanced overall survival.”
These results suggest that gemcitabine successfully primes PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation, only following the disruption of the immunosuppressive cytokine barrier, Principe said.
“Given the lack of third-line treatment options, this approach warrants consideration in the clinical management of gemcitabine-refractory PDAC,” he said.
In addition to the research being featured on the issue’s cover, the journal also published a commentary on the study written by a leading group of pancreatic cancer scientists from the University of Michigan. It discussed the significance and direct therapeutic implications of Rana and Principe’s study, stating that “in addition to providing a path to translation, this article also opens new areas of research.”
Rana and Principe were assisted in the research by Matthew Narbutis, Sandeep Kumar, Alex Park, Navin Viswakarma, Matthew Dorman, and Paul Grippo, all of the University of Illinois College of Medicine; Suneel Kamath, Feinberg School of Medicine, Northwestern University, Chicago; Melissa Fishel, Indiana University School of Medicine, Indianapolis; Rosa Hwang, MD Anderson Cancer Center, Houston; Dinesh Thummuri, Patrick Underwood, and Jose Trevino, University of Florida, Gainesville; and Hidayatullah Munshi, Feinberg School of Medicine, Northwestern University, and Jesse Brown VA Medical Center, Chicago. Rana is also affiliated with the Jesse Brown VA Medical Center.
The work was supported by Veterans Affairs Merit Award I01BX002703 and Career Scientist Award IK6 BX00485 to Rana; by NIH F30CA236031 to Principe; and by NIH R01CA217909 and Veterans Affairs Merit Award I01BX002922 to Munshi.