Breaking Barriers: How Immunotherapy Targets Pancreatic Cancer

Cancer immunotherapy has helped transform treatment for patients with 29 forms of cancer. Some cancer types, like lung and skin, are much easier to treat today thanks to immunotherapy’s immense power to channel the immune system to eliminate cancer. However, pancreatic cancer is one type of cancer that has proven a more difficult challenge for scientists. As the third-leading cause of cancer related deaths in the U.S., pancreatic cancer is a devastating disease whose patients can benefit from immunotherapy research. 

The cancer cells are plastic and can rapidly adapt to changing environments thereby escaping therapeutic pressure.”

–Dr. Chiara Falcomatà, CRI Postdoctoral Fellow

Immunotherapy’s Inroads Against One of the Deadliest Cancers 

Immunotherapy innovation against pancreatic cancer is urgently needed to address unmet patient needs. Pancreatic ductal adenocarcinoma (PDAC) is responsible for 90 percent of pancreatic cancer diagnoses, and there is a 13 percent five-year survival rate among patients. Chiara Falcomatà, PhD, with the Icahn School of Medicine at Mount Sinai, a CRI Postdoctoral Fellow, told CRI that there have been some recent breakthroughs that can help current and future pancreatic cancer patients. Dr. Falcomatà explained that mRNA vaccines targeting cancer-specific biomarkers have helped boost post-surgery immune responses in pancreatic cancer. 

“Additionally, programmed cell death protein 1 (PD-1) blocking antibodies, such as pembrolizumab and nivolumab, are approved to treat the two-to-three percent of PDAC patients whose tumors exhibit high mutational burden due to microsatellite instability (MSI),” she said. These tumors experience a higher rate of genetic mutation due to errors in repeating sequences of DNA, and these unchecked errors can eventually lead to cancer.

Other scientists agree with Dr. Falcomatà’s assessment that pancreatic cancer is both complex and very deadly. Elana Fertig, PhD, division director of oncology quantitative sciences, associate cancer center director of quantitative sciences, co-director of the Convergence Institute, co-director of the Single-Cell Training and Analysis Center, and professor of oncology at Johns Hopkins School of Medicine, told CRI that understanding the complexities of the disease and targeting it during the early stages could provide the best outcome for patients.

However, Dr. Fertig also mentioned significant advances in the fight against pancreatic cancer, including vaccine strategies, chemo-immunotherapy combination treatments, and checkpoint inhibitors that take the ‘brakes’ off the immune system to unleash its full power against cancer. She emphasized that fixing the detection problem could go a long way to improving patient outcomes. During a recent webinar about artificial intelligence and cancer immunotherapy, Dr. Fertig said, “We’re at a point where we have hope for treatments in later stage pancreatic cancer, but the more we can do to transition those into earlier-detected tumors, the better off patients are going to be.”

An Unpredictable and Evasive Disease 

Subtle symptoms are one of the main factors responsible for pancreatic cancer’s high diagnosis and mortality rate. To start, there is no broadly used detection method. Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center of the University of Pennsylvania, CRI Scientific Advisory Council member and Clinical Accelerator Investigator, told CRI in June that detection for pancreatic cancer can be very difficult, especially in the early stages. 

“Very often, patients I meet will have fatigue as their only symptom, or some vague pain in their stomach,” Dr. Vonderheide said. When a tumor blocks a bile duct, it can lead to jaundice, which can cause the whites of the patient’s eyes and their skin to turn a shade of yellow. Otherwise, the disease can be extremely subtle, he explained. 

This difficulty with vague symptoms can lead to challenges with detecting the cancer itself. Dr. Vonderheide stated that while imaging can help determine if there is a suspicious mass in the pancreas, the bigger clue lies in a tissue sample. As with other cancers, outcomes are better when the disease is caught early and before it can spread. However, Dr. Vonderheide explains that catching pancreatic cancer early be difficult. 

“In half of cases of pancreatic cancer, it has already spread,” he explained. Regarding surgery as a treatment option for pancreatic cancer, he said “We can talk to the patient about being cured of pancreatic cancer if it’s local, small, and we can remove it.” 

In addition to obstacles around diagnosis and detection, pancreatic cancer presents challenges for researchers because of a hostile tumor microenvironment (TME) Dr. Falcomatà said that despite recent immunotherapy breakthroughs, just a small number of pancreatic cancer patients have experienced positive treatment responses. 

“Many PDAC tumors contain infiltrating T cells, yet these cells are often inadequately activated within the TME.” she told CRI. “Immune checkpoint inhibitors depend on pre-activated T cells that can be re-engaged by blocking inhibitory pathways, but in PDAC, this approach is largely ineffective due to insufficiently primed T cells.” 

Dr. Falcomatà also stated that every tumor is unique because of the genomic instability involved in pancreatic cancer. Due to this variance that includes distinct “niches” like distinct cell-to-cell communications that help cancer resist treatment, targeted approaches could possibly succeed where clinical trials have failed. Future research needs to address not only the cancer itself, but the surrounding TME to benefit patients with unmet needs. 

The Path Forward 

CRI-affiliated scientists are applying their laboratory expertise against pancreatic cancer to help make this dangerous disease more easily treatable with immunotherapy. Dr. Falcomatà anticipates future breakthroughs will involve combination immunotherapies, vaccines, and checkpoint inhibitors. In June 2024, she co-authored a research paper that established a novel chemical structure for developing a compound to target AMP-activated protein kinase (AMPK), an enzyme that helps regulate energy balance. This kind of research is critical to opening new therapeutic options and avenues for research into this devastating cancer.  

Given pancreatic cancer’s unpredictable nature, both Drs. Falcomatà and Fertig stressed that personalized therapies could make headway where some clinical trials failed. Thanks to the tireless research efforts and advocacy of Drs. Falcomatà, Fertig, and Vonderheide, we strive closer to creating a world immune to cancer.