Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of only 5% to 7%,1 and immunotherapeutic approaches that have shown significant promise in other hard-to-treat tumors like melanoma have so far barely made a dent in survival for PDAC. This is widely believed to be due to immunosuppression within the PDAC tumor microenvironment, which is the subject of 2 research presentations from the 34th Annual Meeting & Preconference Programs of the Society for Immunotherapy of Cancer, or SITC 2019, held in Maryland in early November 2019.
The first abstract describes how PDACs have exceptionally large amounts of vasoactive intestinal peptide (VIP), an immunosuppressive peptide which is known to decrease the proliferation of activated T cells and change their maturation dynamics.2
“We looked The Cancer Genome Atlas to assess the VIP level in all human solid tumors and found pancreatic cancer has the highest,” said Sruthi Ravindranathan, PhD, postdoctoral fellow at the Winship Cancer Institute, Emory University, Atlanta, who presented the work at SITC. The researchers then looked at VIP levels in 10 blood samples from patients with PDAC, finding they were much higher than in healthy controls.
“Why are there high levels of VIP in PDAC? Is it affecting tumor growth or treatment response? It’s so immunosuppressive,” pondered Dr Ravindranathan.
The researchers then used mouse models of pancreatic cancer to test the efficacy of 2 VIP receptor antagonists, ANT-00 or ANT-08, on PDAC tumor growth in vivo when combined with anti–PD-1 therapy.
“We treat the tumors with VIP antagonist, anti–PD-1, or [a] combination of both. The combination is the most successful, the tumors grow very slowly, and we also assess the tumor burden by weighing the pancreas after the mice have been sacrificed,” said Dr Ravindranathan.
The mice treated with the combination had a significant improvement in median survival and had increased CD4+ and CD8+ T-cell infiltration into the tumor microenvironment. So what is next for this promising preliminary work?
“We are trying to clinically translate this work and eventually get to human clinical trials. We have a pipeline and resources available and we are going down that route,” said Dr Ravindranathan, mentioning that work is ongoing to patent the VIP receptor antagonist and improve the stability of the compound.
The second presentation looked at the role of B-cell secreted cytokines in immunosuppression in PDAC, focusing on IL-35 secreted by regulatory B cells.3
“We originally found this cytokine to be expressed in pancreatic cancer cells, in immune cells in mice, and archived patient samples,” said Yuliya Pylayeva-Gupta, PhD, from the Lineberger Cancer Center, University of North Carolina at Chapel Hill, who presented the work at SITC. “We found B lymphocytes infiltrated the tumors in both mice and people. They normally don’t do this; they circulate in the blood and reside in lymphoid tissues,” she added.
IL-35 has previously been implicated in suppressing immune responses in several autoimmune diseases but has not been extensively studied in PDAC.