The successes observed with various immune oncologic treatment approaches have largely bypassed pancreatic cancer, but this may be about to change, based on emerging insights into how and why these tumors evade attacks by T cells. At the 2nd International Cancer Immunotherapy Conference, two experts in the field of pancreatic cancer research and immunology described efforts to bring pancreatic cancer into the fold of those malignancies responding to checkpoint blockade and other immunotherapeutic strategies.1,2
We postulated that these desirable effects of [focal adhesion kinase inhibition] on the microenvironment might render pancreatic ductal adenocarcinoma tumors more sensitive to immunotherapy.— David G. DeNardo, PhD
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David G. DeNardo, PhD, Assistant Professor of Medicine at Washington University School of Medicine, St. Louis, noted: “Current strategies for treating pancreatic cancer are not working. What’s particularly striking to me is our inability to control the disease, even when it’s diagnosed locally. Pancreatic cancer could really benefit from the application of immunotherapy, but checkpoint inhibition, vaccinations, and so forth have not been very effective to date.”
Elizabeth Jaffee, MD, Deputy Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, and a Stand Up 2 Cancer Dream Team leader, commented: “I work in one cancer that does not have much natural immune responsiveness, but I think we will eventually see progress in this and other cancers that do not naturally respond to one or two checkpoint inhibitors on their own…. With the recent advances in molecular technologies and the development of relevant pancreatic cancer mouse models, it is now within our reach to dissect the inhibitory pathways within the pancreatic tumor microenvironment. This will, in turn, lead to new therapeutic opportunities that will eliminate these barriers and convert this deadly cancer into a treatable disease.”
It is now within our reach to dissect the inhibitory pathways within the pancreatic tumor microenvironment. This will, in turn, lead to new therapeutic opportunities that will eliminate these barriers and convert this deadly cancer into a treatable disease.— Elizabeth Jaffee, MD
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These and other researchers in the field are elucidating the molecular mechanisms by which pancreatic ductal adenocarcinoma cells derail antitumor immune responses, identifying targetable immune molecules that will combat protumor properties, and evaluating combinations of immunotherapeutic agents that will enhance the efficacy of this approach in this challenging malignancy.
Why Have Immunotherapies Failed in Pancreatic Cancer?
Dr. DeNardo cited several possible factors that may explain why immunotherapies have failed in pancreatic ductal adenocarcinoma. One possibility is that the mutational burden of this disease is too low and/or that the tumor is immunologically “cold.” However, he believes these factors are not the most critical.
More likely, the lack of efficacy stems from the presence in pancreatic ductal adenocarcinoma of a uniquely immunosuppressive tumor microenvironment that creates a barrier to effective immune surveillance. Another key obstacle appears to be the dense desmoplastic stroma—rich in extracellular collagen—that impedes T-cell infiltration. These two factors combine to create an extensive fibrotic response, which is difficult to overcome and hampers the T-cell response, he said.
Strategies to Boost the Efficacy of Immunotherapies
Drs. Jaffee and DeNardo believe that the ineffectiveness of current immunotherapeutic approaches can be overcome, based on insights emerging about the biology of pancreatic cancer. In tumors that are not naturally responsive to immunotherapies, such as pancreatic cancer, Dr. Jaffee said that methods to induce and enhance T cells are critical to producing a clinically beneficial response. “This is an important next step for immunotherapy in all cancers, and we are on the verge of this,” she exclaimed.
The primary goal of Dr. Jaffee’s Stand Up 2 Cancer Dream Team is to reprogram the tumor microenvironment to better mount a meaningful anticancer immune response. Their trials are focusing on identifying and overcoming novel immunosuppressive pathways within pancreatic ductal adenocarcinoma and on utilizing a T-cell–activating vaccine to prime the immune system (learn more about her research on page 30).
Dr. Jaffee emphasized the need to look beyond two familiar checkpoints—programmed cell death protein (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4)—toward the numerous other checkpoints that undoubtedly play a role in pancreatic cancer immune evasion and tumor progression. Data from The Cancer Genome Atlas suggest there may be as many as 10 different checkpoints in pancreatic tumors plus others that can arise as part of the tumor’s adaptive resistance to treatment. These additional checkpoints must be identified and targeted for T cells to penetrate the tumor and for immunotherapies to work in pancreatic cancer, she explained.
“What I envision in pancreatic cancer—and I am working on the next generation of clinical trials in this area—is that we would biopsy the patient and then start treatment based on whatever checkpoints the patient has. While inhibiting this checkpoint, we would also give a T-cell–inducing agent. If the patient responds, that’s great. If they don’t, we will get another biopsy and look for what we have missed,” said Dr. Jaffee.
Defeating Fibrosis
Dr. DeNardo’s team is tackling the fibrosis that is a hallmark of this tumor. “Our thought was, why not target the symptomatology of the tumor microenvironment to get at pathways in the cancer cell that instruct this profibrotic and immunosuppressive response?” he asked.
Boosting Immune Responses in Pancreatic Cancer
- Pancreatic cancer is not a naturally immunoresponsive cancer and thus far has not been effectively targeted by current immunotherapies.
- Inhibition of focal adhesion kinase appears to render a mouse model more sensitive to the effect of checkpoint blockade, with improvement in survival with the combination of a focal adhesion kinase inhibitor and two checkpoint inhibitors.
His research team is focusing on one of these targets: focal adhesion kinase activity. Focal adhesion kinase is not mutated in pancreatic cancer, but it is overexpressed. “[Focal adhesion kinase] is frequently activated in human pancreatic cancer, and this correlates with the two main barriers that could impede therapeutic efficacy,” he said.
Dr. DeNardo and his team identified hyperactivated focal adhesion kinase activity in neoplastic pancreatic ductal adenocarcinoma cells as a significant regulator of the fibrotic and immunosuppressive tumor microenvironment. It modulates tumor cell migration, invasion, survival, and growth, and it correlates with high levels of fibrosis and poor CD8-positive cytotoxic T-cell infiltration in the stroma.
“When [focal adhesion kinase] is activated, it forms a profibrotic loop…. It exacerbates fibrosis in animal models, and this suggests it could be a target in pancreatic cancer,” he added.
Focal Adhesion Kinase Inhibition
Single-agent focal adhesion kinase inhibition with VS-4718, a novel focal adhesion kinase inhibitor, significantly limited tumor progression and more than doubled the survival in the KPC mouse model of human pancreatic ductal adenocarcinoma, whose tumors are poorly immunogenic.3 “This was striking as compared to high-dose gemcitabine, which had no effect in this model,” revealed Dr. DeNardo.
This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages, and a significant reduction in gene expression of focal adhesion kinase. Focal adhesion kinase inhibition also improved the response to gemcitabine, a finding that forms the basis of a clinical trial evaluating VS-4718 plus gemcitabine/nanoparticle albumin-bound (nab)-paclitaxel (Abraxane).
“We postulated that these desirable effects of [focal adhesion kinase inhibition] on the microenvironment might render pancreatic ductal adenocarcinoma tumors more sensitive to immunotherapy,” Dr. DeNardo continued. Indeed, in accordance with this hypothesis, although dual checkpoint inhibition had no effect on overall survival, the addition of the focal adhesion kinase inhibitor rendered the previously unresponsive animals responsive to anti–PD-1 and anti–CTLA-4 antagonists. This led to a significant increase in survival, with a subset of the animals exhibiting substantial tumor regression and survival out past 6 months. “That was impressive to us,” Dr. DeNardo commented.
Reducing the level of fibrosis in immunosuppressive cells through focal adhesion kinase inhibition appears to allow four to five times more T cells to traffic into pancreatic ductal adenocarcinoma tumors and kill malignant cells, he explained. Focal adhesion kinase inhibition also was shown to improve responses to adoptive T-cell therapy.
These findings led to a phase Ib clinical trial in advanced disease, which will test the regimen of the focal adhesion kinase inhibitor defactinib plus the anti–PD-1 antibody pembrolizumab (Keytruda) and gemcitabine.
Dr. Jaffee’s team is also looking for ways to dismantle the stroma, such as by targeting the CXCR4 checkpoint within it. “If we can alter the amount of stroma with a compound, we can combine it with a T-cell–inducing approach such as a vaccine to see if the T cells can get at the tumor more effectively,” she said. “We have shown this preclinically.” ■
Disclosure: Dr. DeNardo has served as a speaker for Verastem and Adheare. Through a licensing agreement with Aduro Biotech, Dr. Jaffee has the potential to receive future royalties and has also received research funding from Aduro Biotech and Bristol-Myers Squibb.
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