A new drug that regulates the tumor immune micro-environment may create a new immunotherapy-susceptible tumor from one that is resistant when combined with a new strategy, according to a study from Johns Hopkins Kimmel Cancer Center and Oregon Health & Science University. They have suppressed the immune microenvironment around a pancreatic tumor so the tumor can live untouched by the immune system. This means the cancer pulls suppressive cells from outside the tumor and the suppressive cells kill off the T cells that would kill the tumor.
The so-called immune desert environment has also allowed PDA, the most common form of pancreatic cancer, to become resistant to such immune therapies, like those that have created miracles for treating lung and melanoma cancer.
In the 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: nivolumab and an epigenetic drug, entinostat, a histone deacetylase inhibitor (HDACi), are both immunotherapy. However, the combination is studied in a group of 27 previously treated advanced PDA patients.
Among those patients treated with combination therapy, a small subset had a strong response, with tumor shrinkage and no progression of disease for a median of 10.2 months. Also described in laboratory analyses of patient samples taken during the trial was how the drug combination should alter the cellular nature of the tumor environment. Results were published on November 12 in Nature Communications and open doors for future clinical trials to show that this strategy can be effective in treating PDA and other immunotherapy-resistant cancers.
While lead study author Baretti says this was the first time these drugs had been tried in PDA patients’ safety profile was reassuring. “It was profound and durable in a subset of patients.” We now need to better understand how to extend that benefit to a much larger patient population.
In earlier work, Azad and Elizabeth Jaffee, MD, deputy director of Kimmel Cancer Center, found that another HDACi, entinostat, changes the behavior of these suppressive cells and delivers powerful immune T cells to tumors in animal models of PDA, making the tumor environment a hostile ground for the tumor, which is published in forthcoming findings from several years ago about the largest clinical trial ever of immunotherapy alone against patients with advanced PDA had showed a zero response rate for patients. On the other hand, in the new trial, an HDAC inhibitor was pitted against the immunotherapy. 3 of 27 patients had deep tumor shrinkage with the drug combination.
Baretti says, “We will go back and examine more deeply the three patients that responded so deeply and for such a long and see if we can identify other biomarkers that would have predicted this response even more accurately to therapy.” During the trial, clinical and basic researchers got blood and tissue samples from patients. Cellular and molecular studies examining samples with the addition of entinostat were performed to understand further how entinostat affects the tumor microenvironment, including multiplexed immune histochemistry and whole transcriptome RNA sequencing.
Entinostat reprogrammed the tumor microenvironment: It decreased the number of suppressive innate immune cells and increased the activation and proliferation of supportive T cells. The change in that environment, from immunosuppressive to immune responsive, allowed the immunotherapy nivolumab to leverage the immune system to see the tumor cells and kill them. They come back to the bench, and the team will begin to test entinostat, together with additional immune inhibitors and cancer vaccines to determine if the strategy can be expanded to other patients.
Reference: Baretti M, Ludmila Danilova, Durham JN, et al. Entinostat in combination with nivolumab in metastatic pancreatic ductal adenocarcinoma: a phase 2 clinical trial. Nature Communications. 2024;15(1). doi:https://doi.org/10.1038/s41467-024-52528-7
