Pancreatic Cancer, Immunotherapy, and PRINCE: An Interview with Vanessa Lucey, PhD, MBA

Each year, an estimated 460,000 people globally—and 55,000 in the U.S.—are diagnosed with pancreatic cancer. Worldwide, it causes approximately 430,000 deaths annually, including 44,000 in the U.S., where it is the fourth leading cause of cancer-related death. The most common form of the disease is known as pancreatic ductal adenocarcinoma, or PDAC, which accounts for more than 90% of pancreatic cancer cases.

As of March 2019, there were a total of 89 active clinical trials in pancreatic cancer, including 86 combination trials involving 44 different targets, according to the Pancreatic Cancer Immuno-Oncology Landscape analysis performed by the Clinical Accelerator team at the Cancer Research Institute (CRI). One of those combination trials is the phase Ib PRINCE study, the first trial to emerge from the partnership between CRI, the Parker Institute for Cancer Immunotherapy (PICI), and Bristol-Myers Squibb (BMS) that was formed in 2017 in order to accelerate promising immunotherapy to benefit the patients who need them most. This study also involved Apexigen, who provided a novel immunotherapy agent that’s being evaluated.

To learn more about this PRINCE trial for pancreatic cancer patients, I spoke with Vanessa M. Lucey, PhD, MBA, the director of the CRI Anna-Maria Kellen Clinical Accelerator and Venture Fund.

Arthur N. Brodsky, PhD:

Why is pancreatic cancer so hard to treat in general, and why has checkpoint immunotherapy alone been largely ineffective against the disease?

Vanessa M. Lucey, PhD, M.B.A.:

One of the reasons pancreatic cancer is so hard to treat is because it often isn’t diagnosed until it’s already late-stage disease, and these advanced cancers are much more resistant to therapy. In more than half of pancreatic cancer patients, their disease is already metastatic at diagnosis, meaning it has spread to distant organs. Less than 5% of these patients will survive at least five-years.

With respect to immunotherapy specifically, the tumor microenvironment is a big reason why these treatments are ineffective against pancreatic cancer. There are a lot of different elements in the pancreatic tumor microenvironment that drive resistance to a number of therapies, including checkpoint inhibitor immunotherapies, which have been relatively successful against several other cancer types. Essentially, these elements lead to a lack of T cells within pancreatic tumors. Additionally, there is an increase in the number of cells, like myeloid-derived suppressor cells (MDSCs) and stromal-associated fibroblasts, that can act to suppress immune responses. Other tumor microenvironment elements, like hyaluronic acid, can decrease the ability of T cells to infiltrate these tumors.

Learn more about immunotherapy for pancreatic cancer

Arthur N. Brodsky, PhD:

The PRINCE trial involving patients with untreated, metastatic pancreatic cancer combines chemotherapy with two different types of immunotherapy, including one entirely novel approach. How do these different treatments work, and why might they be even more beneficial for patients when used together in combination?

Vanessa M. Lucey, PhD, M.B.A.:

All the patients in this trial received standard-of-care chemotherapy because these patients haven’t yet received any type of treatment. In addition, they received Apexigen’s CD40 agonist, APX005M, at one of two dose levels, with or without the anti-PD-1 checkpoint inhibitor nivolumab, provided by Bristol-Myers Squibb, a PD-1 checkpoint immunotherapy. The idea is to prevent adaptive resistance and promote T cell activation. Finally, patients receive the novel agent—which activates a pathway called CD40—to potentially turn on antigen-presenting immune cells like dendritic cells and macrophages, so that they’re more likely to be stimulated to activate T cells. The rationale for this combination as based off preclinical data generated by lead investigator Robert H. Vonderheide, MD, DPhil, a CRI scientific advisory council member who also serves as the director the Abramson Cancer Center at the University of Pennsylvania and a PICI member scientist.

Arthur N. Brodsky, PhD:

Earlier this year, some pretty positive results from the PRINCE trial were revealed. Can you share them?

Vanessa M. Lucey, PhD, M.B.A.:

In a pre-specified analysis, we looked at a subset of 24 patients who received at least two doses of chemotherapy and at least one dose of the CD40-targeting immunotherapy. Some, but not all, of these patients also received the PD-1 checkpoint immunotherapy. Overall, tumors shrank in 20 of these 24 evaluable patients.

Arthur N. Brodsky, PhD:

Are there any side effect concerns associated with the combination treatment?

Vanessa M. Lucey, PhD, M.B.A.:

The first phase of this study was designed to evaluate dosage and safety of the combination, and we are providing the drugs in sequence to help minimize toxicities. In addition, the immunotherapy agents we are using are thought to work by separate mechanisms and target different pathways, which may help avoid overlapping toxicities.

The preclinical data suggested that there is a synergy between the agents being investigated, and one of the goals of this study is to generate data that helps us understand the underlying mechanism of how the agents may work together, and how they may influence the side effects that can occur in patients.

Arthur N. Brodsky, PhD:

What is the status of the PRINCE trial right now? Are more patients still being recruited for future study?

Vanessa M. Lucey, PhD, M.B.A.:

Right now, we continue to follow the patients treated in the phase 1b portion of the trial, and we’ve completed enrollment for the phase II trial that will further explore the clinical efficacy of this combination treatment. Throughout these trials, we are also performing deep sequencing to determine if there are any biomarkers associated with responses as well as resistance in patients, in order to help us better understand this combination’s mechanisms of action and identify potential targets that might be used in the future to improve patient responsiveness to immunotherapy.

Learn more about the PRINCE trial