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.


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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.

The researchers used 2 main strategies to explore the role of IL-35 in PDAC. First, they generated a mouse model with a knockout of IL-35 in B cells and also used a mouse model with B-cell–specific loss of IL-35 combined with orthotopic PDAC modeling to further explore the role of IL-35.

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“When we deleted IL-35 in B-lymphocytes, the tumors didn’t grow as well. If we block IL-35, the cytotoxic T cells come into the tumors at a much greater frequency than before. Here, we are seeing the immune response and the tumors are much smaller,” said Dr Pylayeva-Gupta.

In addition, they used an IL-35 inhibitor, combined with anti–PD-1 therapy to see whether the mouse PDAC tumors were sensitized to the immunotherapy.

“One of the reasons that people think immunotherapy might be ineffective in some PDAC patients [is that] the cytotoxic T cells need to be present and then activated, for example, by checkpoint blockade. We allowed infiltration of T cells by eliminating IL-35 and then combined with PD-1 to stimulate the immune response,” said Dr Pylayeva-Gupta.

The team plans to continue to work on making the IL-35 blocking reagent they have, which is not currently ready for use in humans.

“We are interested in finding out how these immunosuppressive B cells are produced in cancers and how they make these immunosuppressive cytokines. Maybe this is also relevant for other cancer types — we are looking into that right now,” said Dr Pylayeva-Gupta.

References

1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-2921.

2. Ravindranathan S, Wang S, Ware B, et al. Vasoactive intestinal peptide: a novel checkpoint pathway in pancreatic ductal adenocarcinoma. Presented at: the 34th Annual Meeting & Preconference Programs (SITC 2019); November 6–10, 2019; National Harbor, MD. Abstract O41.

3. Bhalchandra M, Pylayeva-Gupta Y. IL-35+ B cells regulates anti-tumor immune response in pancreatic cancer. Presented at: the 34th Annual Meeting & Preconference Programs (SITC 2019); November 6–10, 2019; National Harbor, MD. Abstract O47.

This article originally appeared on Cancer Therapy Advisor