New drug strategy reverses resistance to immunotherapy in pancreatic cancer
· News-MedicalThe 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 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.
Marina Baretti, M.D., lead study author, the Jiasheng Chair in Hepato-Biliary Cancer at the Kimmel Cancer CenterThis 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."
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.
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.
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