Emerging Immunotherapy and Precision Medicine Strategies Take Aim at PDAC Treatment Resistance

Immunotherapy and precision medicine remain 2 of the most active and challenging areas of investigation in pancreatic ductal adenocarcinoma (PDAC), a malignancy long recognized for its immune-resistant biology and limited responsiveness to existing systemic therapies. In a discussion with OncLive®, Jose Trevino, MD, outlined how emerging strategies that pair immune-based approaches with targeted agents—such as KRAS-directed therapies—may help reverse tumor-driven immune suppression and enhance antitumor activity.

In the first part of the interview, Trevino explored the unmet needs for patients with PDAC, emphasizing gaps in early detection, the high proportion of patients who present with unresectable disease, and the critical role of multidisciplinary care. Building on those themes, Part 2 expanded into how investigational immunotherapy combinations and future precision medicine approaches may push the field forward.

Trevino serves as the chair of the Division of Surgical Oncology at the Virginia Commonwealth University (VCU) School of Medicine and is surgeon-in-chief at the VCU Massey Cancer Center in Richmond. He is also the Walter Lawrence, Jr., Distinguished Professor of Oncology at Massey and is an associate professor in the Department of Surgery at the VCU College of Medicine.

OncLive: Which investigational PDAC management approaches are most promising? What efficacy signals would indicate a meaningful step forward for this historically immune-resistant tumor type?

Trevino: Immunotherapies are great. Immunotherapy is the idea of using particular drugs that are going to help a patient’s own biology and immune system, function stronger and better to kill cancer. Cancer is an abnormal component of who we are, and it’s an abnormal growth, even though it comes from us. Something went wrong within 1 cell that ultimately led to the development of [millions] of abnormal cells that the body knows are not in a good place.

Cancer—[specifically] PDAC—has a way to manipulate the immune system: to shut it down, to block it, to not allow it to penetrate [and] kill this type of cancer. It’s evasive on that level. Immunotherapies on their own have not worked well for PDAC. This cancer is smart.

As we think about therapies, as we consider KRAS inhibitors and other targeted therapies, the idea is that we shut off the cancer’s ability to manipulate the immune system. [If] we allow the immune system to attack the cancer and kill the PDAC cells, [that’s] exciting.

There are ways we can shut down that manipulative attitude of PDAC cells. We might allow the immune system to be more effective, and in the presence of an immunotherapy, [to] drive the immune system to kill it even further. That is exciting. Now we’re using the patient’s own body and giving it a bit of a push. If we’re suppressing the ability of that cancer to control the immune system, it’s a win-win. It makes sense.

Immunotherapies in other cancers have worked wonderfully. [Immunotherapy in] melanoma [has] transformed the field. In lung cancer, [immunotherapy has] pushed toward patients surviving long with their diseases. But in pancreatic cancer, it’s a different beast. Therefore, with new targeted therapies, we may control pancreatic cancer’s way of manipulating the body’s own systems.

How is precision medicine shaping current treatment selection in pancreatic cancer? What future innovations could help expand the feasibility of personalized therapy for a broader group of patients?

Personalized medicine is the way to go. I wish I had the ability to transform my ideas into action and bring a way to analyze one patient’s tumor and tell you that this patient would benefit from [certain] drugs, systemic therapies, and targeted therapies, [as well as whether they need] radiation. That would be key. We’re years away from that.

But [as much as] we are special as individuals, we are also special within our own groups. There is a lot of consideration for diverse patient populations—where patients come from and what their genetic background is. It’s powerful because when we start to break down genetic ancestry, there are certain vulnerabilities and certain strengths among different groups in different cancers. For example, if you look historically at cancers that develop in certain patient populations vs others, you’ll see that there are certain cancers that are predominantly in Black patients vs certain cancers that are predominantly in White patients. There are also certain cancers where there is a therapeutic advantage of a patient’s ancestry being from a particular part of the world.

It gets even more complicated as you start to dive deeper into the individual patient—not only their genetic [background] and ancestry, but also: Is the primary tumor different from the tumor that goes to the liver or lungs? You personalize the treatment approach to the primary tumor, but does that mean it’s going to affect the possibility of that tumor going to the liver or the lung? Is that a disease that’s different? This is important and what the personalization of cancer will be one day.

[If a patient has] a cancer, we will be able to take a piece of tissue from where it started. [For instance, we might] take a biopsy from the pancreas and [see that] it has particular proteins that are upregulated and particular genes that are mutated. [From that, we will] know there are [specific] drugs that might help.

[Once the patient completes that treatment] and gets to surgery, [they may live] 5 years without cancer recurrence. Suddenly in the sixth year, there may be a tumor in the liver that is a metastasis that recurs. Then you could take a biopsy of that, and [see that it is a] new development of a new tumor. [You might] look at this tissue from the liver and know that if you look at certain proteins and genetic mutations and they’re similar [to those in the primary tumor], you [can treat the patient] with the same drug or a different drug. That’s personalizing [treatment to] the primary disease and the metastatic disease. [In that way, you might] continue to kill the disease. Every time it wants to bounce back, you can characterize it again, kill it again, and move forward. [Patients may] live longer lives.

It’s not just about living. Many patients with cancer would agree with is that it’s also [important to have a] good quality of life. If we develop targeted therapies for these cancers, [we hope] that the adverse effect profile is much lower than those of the standard chemotherapies we give today, so patients can live happier, longer, quality lives.