New drug strategy reverses resistance to immunotherapy in pancreatic cancer

Johns Hopkins MedicineNov 14 2024

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 around a pancreatic tumor has suppressed immune activity, allowing the tumor to evade attacks by the immune system. The cancer evades the immune system by attracting suppressive cells into the tumor, which limits access of tumor-killing T cells. Because of that 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 Nilofer Azad, M.D., professor of oncology and co-leader of the Kimmel Cancer Center's Cancer Genetics and Epigenetics Program, and Marina Baretti, M.D., the Jiasheng Chair in Hepato-Biliary 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 those patients, the combination resulted in a strong response with tumor shrinkage and no disease progression for a median of 10.2 months. Additionally, laboratory analyses of patient samples taken during the trial provided insights into how the drug combination worked on the tumor microenvironment level.

The results, published Nov. 12 in Nature Communications, create a road map for using this strategy in future clinical trials for PDA and other immunotherapy-resistant cancers. 

This was the first time that we combined these drugs in patients with PDA, and we were reassured by the safety profile. 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."

Marina Baretti, M.D., lead study author, the Jiasheng Chair in Hepato-Biliary Cancer at the Kimmel Cancer Center

Prior work led by Elizabeth Jaffee, M.D., deputy director of the Kimmel Cancer Center, and Azad, found that the drug entinostat -; an HDACi known to modify gene expression patterns -; altered the activity of suppressive immune cells and recruited powerful immune T cells to tumors in animal models of PDA, converting the environment around a tumor from an immune desert into an active immune battleground. In an earlier study, they found that the combination of entinostat and nivolumab significantly improved survival in mice treated with both agents, as compared with mice treated with either agent alone.

Translating those findings to the clinic, Baretti, Jaffee, Azad and team planned a phase 2 trial testing the drug combination in patients with advanced PDA. Several years earlier, in published findings on the largest clinical trial to date of an immunotherapy alone against PDA, patient response rate was zero. In contrast, in the new trial combining an HDAC inhibitor with the immunotherapy, 3 of 27 patients had deep 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 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.

During the trial, the team of clinical and basic researchers collected blood and tissue samples from 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 activation and proliferation of helpful T cells in the area. That shift in the environment, from immunosuppressive to immune-responsive, allowed the immunotherapy, nivolumab, to work, recruiting T cells to attack the tumor cells. 

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

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

Additional co-authors on the study 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 & Science University also contributed.

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

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