Unlocking Immunotherapy: Insights from Lustgarten-Funded Leaders

Studies referenced are supported by the Lustgarten Foundation’s Robert F. Vizza Clinical Accelerator Initiative (CAI)

Cancer immunotherapy is the use of the immune system to prevent or treat cancer. Unlike chemotherapy or radiation, it is a type of treatment that boosts the body’s natural defenses to fight cancer. It uses substances made by the body or in a laboratory to improve or restore immune system function. Through this therapy, the immune system is guided to attack and kill the cancer cells. Immunotherapy has been very successful in treating other types of cancer, which is why pancreatic cancer experts believe it has promise.  

Gregory L. Beatty, MD, PhD, Associate Professor of Medicine (Hematology-Oncology) at the University of Pennsylvania Perelman School of Medicine
In this interview, Dr. Beatty discusses how he will test a new combination immunotherapy approach bringing together two drugs, one targeting CD40 and the other targeting Dectin-1, to activate the immune system against pancreatic cancer, in his study “Combinatorial myeloid activation as immunotherapy for metastatic pancreatic cancer.”

How does this combination of immunotherapy agents differ from other combinations that have been used before?

“This combination differs from previous immunotherapy strategies by focusing on dual myeloid agonists rather than relying on traditional T cell–activating agents. Most prior approaches have used a single myeloid agonist alongside checkpoint inhibitors to enhance T cell responses, but this study investigates whether two myeloid-targeting antibodies alone can drive a meaningful anti-tumor effect. In pre-clinical models, the combination showed a strong synergistic immune response that neither agent could achieve alone. Encouraged by those results, a small clinical study was conducted in pancreatic cancer patients, where early signs of activity—partial response in one patient and stable disease in another—suggested potential. This is a novel approach in a cancer type largely resistant to standard immunotherapies. If confirmed in larger trials, this strategy could redefine how we use the immune system to treat pancreatic cancer.”

Do you think there will be a difference in response between patients who progressed on chemotherapy versus those with stable disease?

“This study is designed to explore how prior response to chemotherapy might influence the effectiveness of immunotherapy. While we are not including patients whose cancer has progressed on first-line chemotherapy, we are stratifying participants into two groups: those with stable disease and those who have shown a measurable response. Our hypothesis is that patients who respond to chemotherapy may have a more active immune system and could be more likely to benefit from immunotherapy. However, we also believe that patients with stable disease may still possess immune potential that could be harnessed by this treatment. This is one of the first studies to use chemotherapy response as a stratification tool, and it may offer important insights into which patients are more likely to benefit from immunotherapy. Ultimately, we hope to identify biological or immune features within each group that could guide future treatment decisions.”

Would this combination therapy help patients who have not received chemotherapy?

“This study is limited to patients who have already received first-line chemotherapy, so we won’t be able to assess how the combination therapy works in those who are treatment-naïve. However, it raises an important question about how we can move toward more durable responses in pancreatic cancer. Chemotherapy, while often effective in the short term, typically leads to limited and short-lived benefits. Even newer targeted therapies—like those aimed at KRAS mutations—have shown promise but tend to lose effectiveness over time. The goal of this study is to explore whether activating the immune system can offer a more sustained approach to disease control. If successful, this strategy could eventually be tested earlier in the treatment course, potentially even as a first-line option. Ultimately, we hope it will lead to longer-lasting outcomes that go beyond initial tumor shrinkage.”

What impact do you think this study will have for the PDAC community?

“This study has the potential to significantly impact the pancreatic cancer (PDAC) community in several key ways. First, it aims to address the challenge of short-lived treatment responses by engaging the immune system to achieve more durable disease control—something traditional therapies have struggled to provide. Second, it introduces a more personalized approach by stratifying patients based on their response to first-line chemotherapy and investigating biological markers that could help predict who benefits most from immunotherapy. This could lead to more tailored, effective treatments in the future. Third, the study proposes a shift in treatment strategy—moving from continuous chemotherapy to a phased model that uses chemotherapy for induction, followed by a maintenance phase focused on immunotherapy. This approach may reduce toxicity while enhancing immune engagement. Collectively, these innovations could improve both survival outcomes and quality of life for patients with PDAC. If successful, this study could help redefine how we treat and manage this challenging disease.”

Katie Bever, MD, Assistant Professor of Oncology at Johns Hopkins University School of Medicine
In this interview, Dr. Bever gives an overview of how her team, co-led by Dr. Bever and Dung Le, MD, Professor of Oncology, is investigating the efficacy of immunotherapy combinations with a FOLFIRINOX chemotherapy backbone in controlling metastatic pancreatic cancer and stimulating the immune system to recognize cancer cells, in the study “NC410 and FOLFIRINOX in Combination with Anti-PD-1 with and without Anti-CTLA-4 for Treatment Naive Metastatic Pancreatic Cancer.”

What role does collagen have in the pancreatic tumor microenvironment?

“Collagen plays a complex and somewhat controversial role in the pancreatic tumor microenvironment. Pancreatic cancer is known for its dense, fibrotic stroma, largely composed of collagen, which creates a physical barrier around and between tumor cells. This barrier can impede drug delivery and limit immune cell infiltration, making tumors more resistant to both chemotherapy and immunotherapy. While some studies suggest that collagen might help contain tumor growth, mounting evidence indicates that it also contributes to immune suppression. A key mechanism involves collagen binding to a receptor on immune cells called LAIR-1, which sends an inhibitory signal that dampens immune activity—functioning similarly to other immune checkpoints. In our study, we’re testing a drug called NC410, which blocks this interaction between collagen and LAIR-1. The goal is to both remodel the stroma and release the immune suppression caused by collagen, thereby enhancing the body’s ability to mount an anti-tumor response. This approach offers a novel way to overcome one of the key barriers to effective treatment in pancreatic cancer.”

What was the rationale behind the combination of anti-PD-1, anti-CTLA4, and NC410? Is one not enough to elicit an effect?

“The rationale for combining anti–PD-1, anti–CTLA-4, and NC410 stems from the recognition that no single immunotherapy agent has shown consistent benefit in pancreatic cancer when used alone. While our group and others have tested anti–PD-1 and anti–CTLA-4 antibodies individually, responses have been rare. However, combining these two agents has demonstrated modest but encouraging activity, suggesting potential synergy between the pathways they target. NC410 adds another layer by targeting the tumor microenvironment—specifically, it blocks collagen’s interaction with the immune-inhibitory receptor LAIR-1, which can suppress immune responses. By addressing both immune checkpoints and the suppressive stroma, this triple combination aims to overcome multiple barriers that have limited immunotherapy effectiveness in pancreatic cancer. Additionally, the regimen is paired with standard chemotherapy, which may help release tumor antigens and further prime the immune system. The combination reflects a multi-pronged strategy designed to enhance immune activation where single agents have fallen short. A key objective of the study is to understand which patients are most likely to benefit and why.”

Is there a particular patient population that would have the best response?

“One of the central goals of this study is to identify which patients are most likely to benefit from this novel combination of chemotherapy and immunotherapy. We believe that not all patients respond the same way, and there may be a specific subset with biological features that make them more responsive to this approach. To explore this, we’ll be collecting and analyzing tumor biopsies and blood samples to look for predictive biomarkers. Prior research suggests that certain genetic traits—such as defects in DNA damage repair pathways—may be associated with better responses to immunotherapy. However, because this is a new combination strategy, it’s important to investigate these associations in the context of this specific regimen. The study is designed to provide insight into both clinical outcomes and the underlying biology driving response. Ultimately, our aim is to use these findings to refine patient selection in future trials and move toward more personalized treatment approaches for pancreatic cancer.”

Kevin C. Soares, MD, Assistant Attending Surgeon of Hepatopancreatobiliary Surgery at Memorial Sloan Kettering Cancer Center (MSKCC)
In this interview, Dr. Sores discusses his multi-institutional trial that will evaluate the safety and efficacy of ELI-002 7P, an anti-KRAS vaccine, combined with chemotherapy, with or without anti-PD-1 therapy; the bases of his study “A Pilot Study of Neoadjuvant mFOLFIRINOX and ELI-002 7P with or without Anti-PD-1 Checkpoint Blockade in Borderline and Resectable Pancreatic Ductal Adenocarcinoma.”

Do you think vaccines will be the future of PDAC treatment?

“I do believe vaccines have a growing and potentially transformative role in the future of pancreatic cancer (PDAC) treatment. For many years, PDAC was considered resistant to immune-based therapies, but we’re now entering a promising era where that assumption is being challenged. Recent clinical trials have shown early but encouraging signals that vaccine-based therapies can help activate the immune system against pancreatic tumors. This study is designed to build on those signals by evaluating how vaccines can be integrated into current treatment strategies. The ultimate goal is to move beyond temporary disease control and toward more durable responses. Vaccines may be particularly valuable when combined with other immunotherapies or used in specific windows—such as after chemotherapy, when the immune environment may be more receptive. While we’re still early in the journey, the science is rapidly evolving, and I believe vaccine-based strategies will become an increasingly important part of how we treat PDAC in the future.”

Will this combination with the anti-KRAS vaccine help prevent metastasis?

“Preventing metastasis is one of the greatest challenges in treating pancreatic cancer—and it’s also one of the most critical. Even patients who undergo surgery, which offers the best chance for a cure, often experience recurrence in the form of metastatic disease. Once metastasis occurs, curative options are no longer available. That’s why the goal of this study is to explore whether combining the anti-KRAS vaccine with other immunotherapies can help the immune system recognize and eliminate microscopic tumor cells before they spread. This trial is a meaningful step in that direction, particularly because it focuses on patients with a high potential for surgery and long-term benefit. In addition to evaluating clinical outcomes, we’re also deeply analyzing what the vaccine is doing at the tumor level—looking at immune activation and tumor biology. These insights will be key to understanding whether this approach can truly reduce the risk of metastasis and improve long-term survival. While we don’t have definitive answers yet, the potential is exciting and worth pursuing.”

What is the benefit of using this vaccine compared to the standard chemotherapy and other immunotherapy agents?

“Standard chemotherapy remains the backbone of treatment for pancreatic cancer, but its effects are often temporary, and recurrence is common—even in patients who undergo surgery and have no visible disease afterward. Immunotherapy agents like PD-1 and PD-L1 inhibitors have revolutionized treatment for other cancers, but they’ve shown limited success in pancreatic cancer when used alone. This trial is exploring a different approach: combining a cancer vaccine with a checkpoint inhibitor to help the immune system better recognize and target pancreatic cancer cells. The vaccine is designed to “train” the immune system to identify tumor-specific signals, while the checkpoint inhibitor removes the brakes that prevent immune cells from acting. This dual strategy may be more effective at eliminating microscopic residual disease that chemotherapy and surgery can’t reach. The goal is not just to shrink tumors, but to create an immune response that can provide long-term surveillance and prevent recurrence. If successful, this combination could offer a more durable and proactive form of treatment than existing options.”