Dougan Discusses Augmenting T-Cell Activity in Pancreatic Cancer

Stephanie K. Dougan, PhD

Pancreatic ductal adenocarcinoma (PDAC) is rapidly metastatic and has proven to be largely unresponsive to current checkpoint blockade, said Stephanie K. Dougan, PhD. However, ongoing research aimed at priming tumor-specific T cells may lead to increased immunogenicity in pancreatic cancer, as well as other poorly immunogenic malignancies.

“We’ve been thinking about ways to augment T-cell priming to poorly immunogenic tumors,” said Dougan. “Checkpoint blockade operates by de-inhibiting T cells. You can take the breaks off of the immune system, but this means that you have T cells there to begin with. Although this tends to be true for many [patients with cancer], it's not true for all patients.”

In a study presented at the 2018 SITC Annual Meeting, Dougan and her colleagues evaluated the effects of the inhibitor of apoptosis protein (IAP) antagonist, LCL-161, in syngeneic models of pancreatic cancer. Although the immunoregulatory antagonist had no effect on subsequent tumor cell death, it led to an increase in NF-κB2 signaling, stimulating surrounding stromal T cells.

OncLive: What are the limitations of the treatment approaches for patients with pancreatic cancer?

What do we know about the potential for immunotherapy in pancreatic cancer?

In terms of immunotherapy, what is the focus of current research efforts?

What have you found with your research?

What other research efforts are you involved in?

What are some challenges specific to pancreatic cancer that need to be overcome?

In an interview with OncLive, Dougan, an assistant professor of microbiology and immunobiology in the Division of Immunology at Harvard Medical School, and a researcher at Dana-Farber Cancer Institute, provided further insight on the study and discussed other research aimed at assessing ways of augmenting T-cell immunity in pancreatic cancer.Dougan: Pancreatic cancer has a very dismal prognosis. It's rapidly metastatic and has a 5-year survival rate under 10%. It's one of the more recalcitrant cancer types. The current standard of care is combination chemotherapy with either gemcitabine and nab-paclitaxel (Abraxane) or FOLFIRINOX. Neither of these regimens extend life all that much. We've been thinking about how to extend the promise of immunotherapy to a disease that has been refractory to all types of therapy, including current checkpoint blockades.Many immunotherapies have been evaluated in pancreatic cancer; they tend to fail. The existing challenges are numerous. One of the questions that my lab studies is why pancreatic cancer is so difficult [to treat] and how we can overcome that. If we make progress in the “worst of the worst” kind of cancer, [we believe that knowledge] will extend to other tumor types as well as where we see less response.Many cancer patients don't have tumor-specific T cells that are waiting to attack the tumor. Therefore, we have been thinking about how to get that T-cell response in the first place and how to augment T-cell priming. Figuring out how to prime the T cells to begin with is really the inverse of checkpoint blockade.We've been looking at augmenting co-stimulation. We have a small molecule that induces noncanonical NF-κB2 signaling. This acts similarly to co-stimulation through TNF family receptors. We've been able to provide this signal to T cells, so that you can augment the priming of T cells of lower affinity, or T cells that see less abundant antigens.We've been looking at combination therapies that augment T-cell priming in addition to chemotherapy and therapies that target myeloid cells. We've also been looking at this in other poorly immunogenic cancer types such as breast cancer, so that we can figure out which immunotherapies synergize particularly well and how we can take that to other tumor types.The disease is rapidly metastatic. Even pancreatic cancer patients who come out of resection with clean surgical margins still have a 60% chance of relapse. Even when the tumor is very small, it's already seeding circulating tumor cells in the body that can form micrometastases.

What is your take-home message on cancer immunotherapy?

How do you kill each and every last cancer cell? I'm not sure we can do this with standard chemotherapy or targeted therapies. We've been thinking about using T cells as a way to find micrometastases. This is what the immune system does best; it patrols the body, it surveys for danger, and it has long-term memory. It would be able to find all of these sites of dormant tumor cells that eventually grow and form metastases.To understand cancer immunotherapy, [you need] a deep understanding of basic immunology; that is to say how tumor cells die and how those tumor cell fragments get taken up by dendritic cells. Then, we can try to understand how to augment dendritic cell activation, increase trafficking to draining lymph nodes, and prime T cells to go into the tumor microenvironment.

Trying to move that understanding into clinical practice, especially for some of these poorly immunogenic tumors, has been difficult. This is an area where continued research is important, so that we can yield valuable insights.

[From these findings], I hope people understands that augmenting T-cell co-stimulation is just as important as inhibiting coinhibitory molecules, and, in some cases, even more important. For poorly immunogenic tumors that don't have a good T-cell response to begin with, we can help prime lower affinity antigens that are not necessarily neoantigens but could be self-antigens. By increasing co-stimulation, you can bring more of these T cells into the antitumor pool.

Roehle K, Dougan M, Dougan S, et al. Augmenting immunity with IAP antagonists in PDAC. In: Proceedings from the 2018 SITC Annual Meeting; November 7-11, 2018; Washington, DC. Abstract P467.