A new drug strategy that regulates the tumor immune microenvironment can turn an immunotherapy-resistant tumor into a susceptible one, according to a study by researchers at Johns Hopkins Kimmel Cancer Center and Oregon Health & Science University.

The immune microenvironment around a pancreatic tumor suppressed immune activity, allowing the tumor to evade immune system attacks. Cancer evades the immune system by attracting suppressor cells to the tumor, which limits access to tumor-killing T cells. Because of its so-called immune desert environment, pancreatic ductal adenocarcinoma (PDA), the most common type of pancreatic cancer, has been resistant to immune-based therapies that have successfully treated a variety of other cancers, including melanoma and lung cancer .

In a phase 2 clinical trial, a research team led by Dr. Nilofer Azadprofessor of oncology and co-leader of the Cancer Genetics and Epigenetics Program at the Kimmel Cancer Center and Marina Baretti, MDJiasheng Chair in hepatobiliary cancer at the Kimmel Cancer Center, tested the safety and efficacy of the combination of two drugs: an immunotherapy, nivolumab, and an epigenetic drug, entinostat—a histone deacetylase inhibitor (HDACi). The combination was studied in a group of 27 patients with advanced PDA who had previously been treated with chemotherapy.

In a small subset of these patients, the combination resulted in a strong response with tumor shrinkage and no disease progression for an average of 10.2 months. In addition, laboratory analyzes of patient samples taken during the study provided insights into how the drug combination worked in the tumor microenvironment.

The results, published on November 12 in Communication of naturecreate a roadmap for using this strategy in future clinical trials for PDA and other immunotherapy-resistant cancers.

“It was the first time we combined these drugs in PDA patients and we were reassured by the safety profile,” says Baretti, the study’s lead author. “We saw a deep and durable response in a subset of patients. We now need to better understand how we can extend this benefit to a larger patient population.”

Previous work led by Elizabeth Jaffee, MDdeputy director of the Kimmel and Azad Cancer Center, found that the drug entinostat—an HDACi known to alter gene expression patterns—altered the activity of suppressor immune cells and recruited strong immune T cells to tumors in animal models of PDA, transforming the environment around a tumor from an immune desert into an active immune battlefield. IN A previous study, found that the combination of entinostat and nivolumab significantly improved survival in mice treated with both agents compared with mice treated with either agent alone.

Translating these findings to the clinic, Baretti, Jaffee, Azad and team planned a phase 2 study testing the drug combination in patients with advanced PDA. A few years ago, in published findings in the largest clinical trial to date of a single PDA immunotherapy, the patient response rate was zero. In contrast, in the new study that combined an HDAC inhibitor with immunotherapy, 3 of 27 patients had profound tumor shrinkage from the drug combination.

In future studies, the team hopes to determine why certain patients responded while others did not.

“With an in-depth investigation of the three patients who had this deep and durable response, we will try to see if we can discover specific biomarkers that could have predicted this better response to therapy,” says Baretti.

During the study, the team of clinical and basic researchers collected blood and tissue samples from the patients. To gain a deeper understanding of the effect of entinostat on the tumor microenvironment, they performed cellular and molecular analyses, such as multiplexed immune histochemistry and whole-transcriptome RNA sequencing, on the samples. They found that entinostat reprogrammed the tumor microenvironment by decreasing the number of suppressive innate immune cells while increasing the activation and proliferation of helpful T cells in the area. That change in environment, from immunosuppressive to immune-responsive, allowed the immunotherapy, nivolumab, to work, recruiting T cells to attack tumor cells.

Next, the team plans to move from the bedside back to the bench, expanding their work in the lab to test entinostat in combination with other immune inhibitors and cancer vaccines to see if the strategy can be scaled up to apply to a larger group of patients.

“We hope that the next generation of clinical trials will emerge from this preclinical work,” says Baretti.

Additional study co-authors were 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. Courtney Betts and Lisa Coussens of Oregon Health and Science University also contributed.

The research was supported by the Lustgarten Foundation Investigator Program, the National Cancer Institute, the National Institutes of Health, the MD Anderson Cancer Center SPORE in Gastrointestinal Cancer – Career Enhancement Program, and the Johns Hopkins Cancer Maryland Moonshot Research Grant. .

Baretti has served on advisory boards for AstraZeneca and Incyte. These relationships are managed by Johns Hopkins University in accordance with its conflict of interest policies.