A combination of nivolumab and entinostat has shown promise in turning pancreatic tumors, typically resistant to immunotherapy, into more immune-responsive cancers, according to a study published in Nature Communications. The Phase II clinical trial, led by researchers at Johns Hopkins Kimmel Cancer Center and Oregon Health & Science University, offers insights into modifying the tumor’s immune environment to enhance susceptibility to immune-based therapies.
Overcoming Immunosuppression in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDA), the most aggressive form of pancreatic cancer, creates an immunosuppressive environment that blocks tumor-fighting T cells, allowing the cancer to evade immune detection. Immune-based therapies, effective in treating cancers like melanoma and lung cancer, have historically had little impact on PDA due to this suppressed immune microenvironment.
Phase II Trial Results
In the Phase II trial, 27 patients with advanced PDA, previously treated with chemotherapy, received a combination of nivolumab, an immunotherapy, and entinostat, an epigenetic drug that inhibits histone deacetylase (HDAC). The trial demonstrated promising results in a subset of patients, with three participants experiencing significant tumor shrinkage and a median period without disease progression lasting 10.2 months.
"This was the first time that we combined these drugs in patients with PDA, and we were reassured by the safety profile," said Marina Baretti, MD, an assistant professor of oncology at Johns Hopkins University School of Medicine. "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 studies indicated that entinostat can alter the immune environment in animal models of PDA, transforming the immune-suppressive surroundings into an active battleground by reducing suppressive immune cells and recruiting tumor-killing T cells. Earlier research showed that mice treated with both entinostat and nivolumab experienced significant survival improvement compared to those treated with either drug alone.
The current trial's combination approach resulted in deep tumor shrinkage in three of 27 patients, marking an important step in exploring immune-based therapies for PDA, contrasting with previous trials testing immunotherapy alone against PDA, where the response rate was zero.
Impact on Tumor Microenvironment
In-depth cellular and molecular analyses, including multiplexed immune histochemistry and RNA sequencing, revealed that entinostat reprogrammed the immune landscape, decreasing the number of suppressive immune cells and increasing the presence and activity of T cells. This shift allowed nivolumab to better recruit T cells to attack the tumor.
Identifying Predictive Biomarkers
Baretti emphasized the importance of understanding why only some patients responded to the treatment. "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," she said. Identifying these biomarkers could help select patients most likely to benefit from the therapy.
Future Directions
The team plans to return to preclinical work, testing entinostat in combination with other immune-targeting therapies and cancer vaccines, aiming to expand the treatment’s effectiveness and develop next-generation clinical trials for a broader group of patients with pancreatic cancer. "We hope from this preclinical work, the next generation of clinical trials will emerge," Baretti said.
