A groundbreaking drug strategy that targets the immune microenvironment around tumors may enable cancers resistant to immunotherapy to become treatable, as shown in a recent study.
A new drug strategy that regulates the tumor immune microenvironment may transform a tumor that resists immunotherapy into a susceptible one, according to a study by researchers from the Johns Hopkins Kimmel Cancer Center and Oregon Health & Science University.
The immune microenvironment surrounding a pancreatic tumor often stifles immune responses, which allows the tumor to evade immune destruction. This occurs because the cancer recruits suppressive cells to the tumor site, restricting the ability of T cells that kill tumors to access it. As a result, pancreatic ductal adenocarcinoma (PDA)—the most prevalent form of pancreatic cancer—has shown resistance to immune therapies that have been effective in treating other types of cancer like melanoma and lung cancer.
In a phase 2 clinical trial led by Nilofer Azad, M.D., a professor of oncology and co-leader of the Cancer Genetics and Epigenetics Program at the Kimmel Cancer Center, along with Marina Baretti, M.D., the Jiasheng Chair in Hepato-Biliary Cancer at the Kimmel Cancer Center, researchers evaluated the safety and effectiveness of a drug combination. This included an immunotherapy drug, nivolumab, and an epigenetic agent, entinostat—classified as a histone deacetylase inhibitor (HDACi). The combination was examined in a cohort of 27 patients diagnosed with advanced PDA who had previously undergone chemotherapy.
Among a small group of these patients, the combination therapy led to substantial tumor shrinkage and no disease progression for an average of 10.2 months. Furthermore, laboratory analyses of samples taken from patients during the trial provided valuable insights into how this drug combination influenced the tumor microenvironment.
The findings, published on November 12 in Nature Communications, outline a framework for future clinical trials targeting PDA and other cancers that resist immunotherapy.
“This marked the first time we tested these drug combinations in PDA patients, and we were pleased with the safety profile,” stated Baretti, the main author of the study. “Some patients exhibited a significant and lasting response. Our next step is to determine how we can extend these benefits to a broader patient group.”
Previous research conducted by Elizabeth Jaffee, M.D., deputy director of the Kimmel Cancer Center, along with Azad, revealed that entinostat—an HDACi that alters gene expression—modified the behavior of suppressive immune cells and attracted effective T cells to tumors in animal PDA models. This transformed the tumor environment from an “immune desert” to an active battlefield against cancer. Their earlier study also demonstrated that the combination of entinostat and nivolumab markedly improved survival rates in mice compared to those treated with either agent alone.
Translating those animal model findings to human application, Baretti, Jaffee, Azad, and their team initiated a phase 2 trial to assess the drug combination in patients facing advanced PDA. In contrast to past results from the largest clinical trial of an immunotherapy alone for PDA, which found no patient responses, the current trial showed that 3 out of 27 patients experienced notable tumor shrinkage when treated with the drug combination.
Moving forward, the research team aims to uncover why some patients responded positively while others did not.
“By closely examining the three patients who had remarkable and lasting responses, we hope to identify specific biomarkers that could indicate a better response to treatment,” Baretti explained.
Throughout the trial, the clinical and research team gathered blood and tissue samples from patients. To gain a more thorough understanding of entinostat’s impact on the tumor microenvironment, they conducted various cellular and molecular analyses including multiplexed immune histochemistry and whole transcriptome RNA sequencing. Their research indicated that entinostat altered the tumor microenvironment by reducing the prevalence of suppressive innate immune cells while boosting the activity and proliferation of beneficial T cells. This transformation from an immunosuppressive to an immune-responsive environment enabled nivolumab to successfully recruit T cells to attack the tumor.
The next step for the team is to return to the laboratory to explore how entinostat can work in tandem with other immune inhibitors and cancer vaccines, with the hope of expanding this approach to benefit a larger patient population.
“We envision that this preclinical work could lead to the next generation of clinical trials,” said Baretti.
The study also included contributions from co-authors Ludmila Danilova, Jennifer Durham, Leslie Cope, Dimitrios Sidiropoulos, Joseph Tandurella, Soren Charmsaz, Nicole Gross, Alexei Hernandez, Won Jin Ho, Chris Thoburn, Rosalind Walker, James Leatherman, Sarah Mitchell, Brian Christmas, Ali Saeed, Daria Gaykalova, Srinivasan Yegnasubramanian, Elana Fertig, and Mark Yarchoan of Johns Hopkins, as well as Courtney Betts and Lisa Coussens from Oregon Health & Science University.
This research received funding from the Lustgarten Foundation’s Research Investigator Program, the National Cancer Institute, the National Institutes of Health, MD Anderson Cancer Center’s SPORE in Gastrointestinal Cancer—The Career Enhancement Program, and the Maryland Cancer Moonshot Research Grant to Johns Hopkins Medical Institutions.
Baretti holds advisory roles for AstraZeneca and Incyte, which are managed by The Johns Hopkins University in accordance with conflict-of-interest policies.
