Globally, pancreatic cancer represents the seventh leading cause of cancer-related mortality. Pancreatic ductal adenocarcinoma (PDA) is generally associated with poor outcomes, despite advancements in targeted therapies and improved understanding of relevant biomarkers for early detection (World J Gastroenterol 2018;24(43):4846-4861). The only potential cure is surgical resection as well as chemotherapy in the adjuvant setting. Novel therapeutic strategies continue to be studied, with some modest (and promising) results.
In a new study by researchers from the University of Washington, a combined blockade of PD-1 and CXCR4 was found to reactivate endogenous tumor-reactive T cells present in human pancreatic tumors (Clin Cancer Res 2019 doi:10.1158/1078-0432.CCR-19-0081). Based on the findings, the combination regimen has potential as an immunotherapy approach for pancreatic cancer, particularly if the findings can be replicated on a larger scale in future clinical trials.
"One of the things many people in the field think about pancreatic cancer is that it's a carcinoma that doesn't typically feature many immune cells that enter the tumor, and if there are immune cells they're primarily suppressive," corresponding study author, Venu G. Pillarisetty, MD, Associate Professor of Surgery at UW Medical Center, told Oncology Times. "In this study, we do a lot of work to lay the stage in suggesting there may be potential anti-tumor activity in some of the immune cells, like the T cells, in the tumor."
Study Details
Using multiplex immunohistochemistry (mIHC) and T-cell receptor (TCR) sequencing, the researchers collected and analyzed preserved human PDA specimens. The effects of a combination of PD-1 and CXCR4 blockade were tested on fresh tumor samples. mIHC found fewer CD8+ T cells in juxtatumoral stroma featuring cancer cells compared with stroma lacking these cells. Clonal expansion was found in each tumor based on TCR sequencing. There were multiple DNA rearrangements in high-frequency clones that coded for the same amino acid binding sequence. When researchers treated the human PDA slices with the PD-1 and CXCR4 blockade combination, they found increased tumor cell death as well as expansion of lymphocytes.
In their study, the investigators were surprised at the results because they weren't entirely sure where they would end up. "There were multiple parts to the study and a lot of it was just trying to understand what the immune microenvironment looked like," Pillarisetty added.
"We found there actually are quite a few CD8+ T cells, and they have the ability to kill cancer cells, meaning they're specific to some sort of tumor antigen," he said. "We found that there are a lot of these groups of identical cells within the tumor, and we thought that these could be anti-tumor cells. We found that if we combine a standard immunotherapy drug that blocks PD-1, we really didn't get that much activity, but if we combine it with another agent that blocks CXCR4, then we saw the T cells were able to migrate a very short difference to the cancer cells and kill them."
The findings from this trial were compelling and unique in that they were derived from human tumors, rather than an animal model. According to Pillarisetty, this preliminary study allows for the possibility of future clinical trials.
"People have been considering doing a clinical trial combining these drug types, so it's not out of the question," he explained. "There's a lot of PD-1 drugs out there, and several CDX4 drugs are currently being investigated. One of the things we show from our study is that we're hopefully getting people excited about doing this combination in pancreatic cancer where in general a lot of people are saying it's not worth trying."
Limitations of the study include the use of tissue in culture as well as the lack of data on the longer-term impact of this drug combination. To further understand the mechanisms behind the results and to tackle the inherent limitations of their study, Pillarisetty and colleagues are planning more research that examines different parts of the pathway. Currently, the researchers are examining CXCL12 and its binding to CXCR4, factors driving CXCL12 production, the mechanisms involved with CXCR4, and other drugs and combinations that can be used in PDA that are more readily available.
Future Pancreatic Research
One phase II trial from the University of Washington that's led by Pillarisetty involves the use of preoperative lanreotide, a somatostatin analog, for reducing the risk of leakage after pancreaticoduodenectomy or distal pancreatectomy (NCT03174353). The trial will also look at overall morbidity, drain amylase levels, duration of drainage, and daily drain volume.
"In our trial, we're giving a shot of lanreotide on the morning of surgery to see if it reduces the risk of leak," Pillarisetty explained. "Ultimately, it will be preliminary data that may trigger a randomized controlled trial if results are positive."
Brandon May is a contributing writer.
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