A novel therapeutic strategy combining the epigenetic drug entinostat with the immunotherapy nivolumab has shown promise in overcoming resistance to immunotherapy in a subset of patients with advanced pancreatic cancer. The phase 2 clinical trial, conducted by researchers at the Johns Hopkins Kimmel Cancer Center and Oregon Health & Science University, demonstrated that this combination can transform the tumor microenvironment, rendering it susceptible to immune attack.
Reversing Immune Suppression in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDA), the most common form of pancreatic cancer, is notoriously resistant to immunotherapy due to its immunosuppressive microenvironment. Tumors evade immune detection by attracting suppressive cells and limiting the infiltration of tumor-killing T cells, creating an "immune desert." The study, led by Nilofer Azad, M.D., and Marina Baretti, M.D., sought to reverse this resistance by combining nivolumab, an immunotherapy, with entinostat, a histone deacetylase inhibitor (HDACi) known to modify gene expression patterns.
Clinical Trial Results
The phase 2 trial involved 27 patients with advanced PDA who had previously undergone chemotherapy. The combination of entinostat and nivolumab resulted in a strong response in a subset of patients, with tumor shrinkage and disease stabilization for a median of 10.2 months. These findings, published in Nature Communications, suggest a potential new avenue for treating this challenging cancer.
"This was the first time that we combined these drugs in patients with PDA, and we were reassured by the safety profile," said Dr. Baretti. "We saw a profound and durable response in a subset of patients. Now we need to understand better how we can expand this benefit for a larger patient population."
Mechanism of Action
Prior research had indicated that entinostat could alter the activity of suppressive immune cells and recruit T cells to tumors in animal models of PDA. The current study confirmed these findings in humans. Analyses of patient samples revealed that entinostat reprogrammed the tumor microenvironment by reducing the number of suppressive innate immune cells and increasing the activation and proliferation of T cells. This shift from an immunosuppressive to an immune-responsive environment allowed nivolumab to effectively target the tumor cells.
Future Directions
The research team plans to further investigate why certain patients responded to the combination therapy while others did not. By analyzing samples from the patients who experienced a profound and durable response, they hope to identify specific biomarkers that can predict treatment success. Additionally, they intend to explore entinostat in combination with other immune inhibitors and cancer vaccines to broaden the applicability of this strategy.
"With an in-depth investigation of the three patients who had this profound and durable response, we'll try to see if we can tease out specific biomarkers that may have predicted this better response to therapy," Baretti says.
The study underscores the potential of epigenetic modulation to enhance the efficacy of immunotherapy in pancreatic cancer and provides a roadmap for future clinical trials targeting the tumor microenvironment.
