From KRAS to CD40: Advancing Pancreatic Cancer Immunotherapy, ft. Dr. Robert Vonderheide

Dr. Patrick Hwu welcomes Dr. Robert Vonderheide, director of the Abramson Cancer Center and Vice Dean for Cancer Programs at the University of Pennsylvania’s Perelman School of Medicine. Dr. Vonderheide shares his journey from early skepticism about cancer immunotherapy to pioneering work in tumor antigen discovery, vaccine development, and activating the CD40 pathway. He discusses the unique challenges of pancreatic cancer, including its suppressive microenvironment and the role of the KRAS oncogene, and explores strategies combining targeted therapy with immunotherapy to generate effective T-cell responses. Dr. Vonderheide also highlights the promise of early detection and interception, the potential of CD40 agonists, and the importance of mentorship in training the next generation of cancer researchers, emphasizing the collaborative, innovative spirit that continues to drive advances in the field.

Podcast Transcript

Dr. Hwu:
Welcome to ImmunoVerse, a podcast that brings the ever-expanding universe of immunotherapy to life. Through the voices of those advancing this groundbreaking field, I’m Dr. Patrick Hwu, President and CEO of Moffitt Cancer Center and a career immunologist.

In each episode, I sit down with pioneering experts who have shaped the past, present, and future of immunotherapy, uncovering breakthroughs, challenges, and the science driving this lifesaving innovation.

Today, we have with us Dr. Robert Vonderheide, Director of the Abramson Cancer Center and Vice Dean for Cancer Programs at the University of Pennsylvania’s Perelman School of Medicine. He’s also a member of Moffitt Cancer Center’s External Advisory Committee.

Dr. Vonderheide is internationally recognized for his research in cancer immunotherapy, particularly in tumor antigen discovery, vaccine development, and harnessing the CD40 pathway to activate immune responses. His work has significantly advanced how we approach immunotherapy for pancreatic cancer, one of the most challenging malignancies, as well as other solid tumors.

As a physician-scientist and institutional leader, Dr. Vonderheide brings a rare combination of scientific vision, translational rigor, and deep commitment to patient-focused innovation.

Welcome to ImmunoVerse, Dr. Vonderheide.

Dr. Vonderheide:
Great to be here.

Dr. Hwu:
We really appreciate you taking the time today. You’ve been in the field a long time, and we were just talking about how, in the early days, no one really cared about immunotherapy.

Dr. Vonderheide:
Yes, 25 years ago, there was a lot of doubt and pressure to prove that the immune system could fight cancer. It was very challenging. What we realized is that we needed better science—stop guessing and start being mechanistic. Once that happened, the dam eventually burst. And here we are. It’s amazing.

Dr. Hwu:
A lot of early immunotherapy work focused on melanoma, like I did, and renal cancer—tumors that were already responding to cytokine treatments. But you focused on one of the hardest cancers, pancreatic cancer, for which we really have no great answers. What made you focus on that?

Dr. Vonderheide:
Having cared for many patients with pancreatic cancer, it became clear there was a real need to focus on this population. Early successes in melanoma taught us that we couldn’t simply apply the same strategies to pancreatic cancer. We had to go back to the drawing board—develop lab models and understand the biology, which is very different from melanoma.

Dr. Hwu:
Melanoma has a lot of mutations due to UV exposure. Is that why it’s more immunogenic than pancreatic cancer, or are there other reasons?

Dr. Vonderheide:
That’s certainly part of it. Pancreatic cancer has far fewer mutations, so it doesn’t look as foreign to the immune system. Also, unlike melanoma on the skin, pancreatic tumors hide deep within the tissue and create dense scar tissue around the tumor cells. Immune cells often just pass by without recognizing the cancer.

In most pancreatic cancers, there aren’t the T cells that would normally recognize tumors, so it’s almost like the immune system ignores them. This led us to realize that we need to activate an immune response from the very beginning, rather than just relieving suppression. That’s why we started exploring ways to vaccinate patients—activate the earliest immune cells to kickstart the response.

Dr. Hwu:
So the immune system sees the pancreas much like a normal organ—it doesn’t detect it as abnormal.

Dr. Vonderheide:
Exactly. Most pancreatic cancers are driven by the KRAS oncogene. Beyond driving tumor growth, KRAS orchestrates a highly suppressive microenvironment, recruiting immune cells that inhibit the immune response and creating dense connective tissue. From the very first malignant cell, this curtain of suppression forms.

The upside is that these tumor cells haven’t had to adapt to immune attacks yet. If we can remove the immunosuppressive barriers and expose the cancer to the immune system, we can trigger a strong immune response. In lab models, this works, and it’s now moving into clinical trials.

Dr. Hwu:
Are the suppressive cells mostly myeloid-derived suppressor cells, macrophages, or Tregs?

Dr. Vonderheide:
All of the above. Pancreatic cancers exploit these cells to suppress the immune system. KRAS plays a central role in shaping this environment. With new drugs targeting KRAS, we see in models that suppressive cells retreat and T cells flood in to attack the tumor.

Dr. Hwu:
So combining KRAS-targeted therapy with immunotherapy could be key.

Dr. Vonderheide:
Exactly. KRAS inhibitors are powerful, but resistance can emerge. If we engage the immune system simultaneously, we might achieve deeper, longer-lasting tumor regression.

Dr. Hwu:
Do KRAS inhibitors affect immune cells themselves?

Dr. Vonderheide:
Mutation-specific KRAS inhibitors largely spare normal cells, including T cells. PAN-KRAS inhibitors can affect normal cells, but there’s a therapeutic window. So far, it looks possible to inhibit KRAS in tumor cells while allowing immune cells to function.

Dr. Hwu:
Even though pancreatic cancer has few mutations, if you can reduce the immune resistance mechanisms, you might generate a T-cell response. What are those T cells recognizing in pancreatic cancer?

Dr. Vonderheide:
Although there are fewer mutations than in lung cancer or melanoma, there are still targets. Recent studies, not from our group but others, have shown that if you design a vaccine based on those mutations, even if they are few, you can generate an immune response.

Dr. Hwu:
We’ve also done a lot of work with the molecule called CD40 ligand. Can you talk a little about that?

Dr. Vonderheide:
Absolutely. CD40 is a member of the tumor necrosis factor receptor superfamily, which plays a critical role in the immune system. CD40 is expressed on antigen-presenting cells, not T cells. These are the frontline cells that initiate the immune response.

When you activate these cells—particularly dendritic cells—through CD40, they become “super activators.” This is especially important in cancers like pancreatic cancer, where the immune response is so blunted. Anti-CD40 antibodies or ligands activate these dendritic cells to jumpstart the immune system.

In the lab, this works extremely well, although clinical trials have been more challenging. We’ve seen promising results in pancreatic cancer and melanoma, and we’re continuing to advance these approaches.

Dr. Hwu:
Have you tested combining anti-CD40 agonists with KRAS inhibition in the lab?

Dr. Vonderheide:
Yes. We recently published a study in Cancer Discovery. In these laboratory models—not yet human trials—the combination of KRAS inhibitors and immunotherapy was very potent. The most effective immune modulation came from anti-CD40, which further activates dendritic and other frontline cells. The synergy is clear in the lab, and we’re excited to translate it to patients.

Dr. Hwu:
Pancreatic cancer is one of the leading causes of cancer death worldwide. Where do you see the field going in five to ten years? Can we detect it earlier or intervene sooner to reduce mortality?

Dr. Vonderheide:
Early detection is very challenging. Surgery can be curative if the tumor is caught in time, but most cases are diagnosed late. We’re shifting our mindset toward prevention and interception—identifying individuals at high risk, such as those with germline mutations like BRCA2, and targeting the earliest lesions before they become invasive cancers.

Early lesions are much less complex, less shielded by connective tissue and suppressive immune cells, and are therefore more vulnerable. Intervening at this stage could make therapies far more effective. Age is also a risk factor; by their 50s and 60s, many individuals already have early lesions, which could broaden the population eligible for risk-reducing strategies.

While we must continue to fight advanced pancreatic cancer, the biggest impact may come from shifting to prevention and early interception.

Dr. Hwu:
You’re also a leader in cancer research and advise Moffitt Cancer Center. What are your thoughts on mentorship and developing the next generation of scientists?

Dr. Vonderheide:
We face a huge challenge and need the next generation to carry this work forward. Training young researchers is fundamental. At the Abramson Cancer Center, we exchange ideas with other centers, including Moffitt, and share strategies to inspire trainees.

Young researchers are highly motivated and stressed about the future. It’s our responsibility to support them fully—they are the future of cancer research. They have access to tools and technologies we never had, which allows them to work faster and tackle questions more efficiently.

Dr. Hwu:
Yes, they know so much more than we did starting out.

Dr. Vonderheide:
Exactly. And their dedication is inspiring. They engage with patients, bring that experience back to the lab, and push the field forward. When we started, we counted cells one by one with microscopes and hemocytometers. Now, we do single-cell sequencing, analyze millions of cells in seconds, and need computational tools, AI, and machine learning to make sense of the data. Imagine what they’ll discover in the next five to ten years. If we maintain boldness and vision, we will get there.

Dr. Hwu:
Wonderful. Thank you for your leadership, your mentorship, and your work tackling pancreatic cancer. We want to thank our guest, Dr. Vonderheide, for joining us today.

And thank you for joining us on this journey through the ever-expanding universe of immunotherapy. To hear more episodes of ImmunoVerse, make sure to subscribe on your favorite podcast platforms.