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Combining a histone deacetylase inhibitor drug with immunotherapy agents is safe, and may benefit some patients with advanced cancers that have not responded to traditional therapy, according to results of a Phase I clinical trial led by researchers at the Johns Hopkins Kimmel Cancer Center, Bloomberg~Kimmel Institute for Cancer Immunotherapy, and several other centers. The University of Pittsburgh Cancer Institute, Yale Cancer Center, and City of Hope in Los Angeles, participated in study enrollment, and the University of Southern California and University College Cork in Ireland, collaborated on analysis of the data.

Evanthia T. Roussos ... - Click to enlarge in new windowEvanthia T. Roussos Torres, MD, PhD, Elizabeth Jaffee, MD, Roisin Connolly, MBBCh, MD, and Vered Stearns, MD. Evanthia T. Roussos Torres, MD, PhD, Elizabeth Jaffee, MD, Roisin Connolly, MBBCh, MD, and Vered Stearns, MD, studied the role of entinostat in combination with immunotherapy.

During the study, 33 patients with advanced solid tumors received the histone deacetylase inhibitor drug entinostat for 2 weeks. Then, some patients received the immunotherapy agent nivolumab, a checkpoint inhibitor, in combination with the entinostat, while others received both nivolumab and a second checkpoint inhibitor agent, ipilimumab, after the initial dosing with entinostat.


Checkpoint inhibitors, such as nivolumab and ipilimumab, release important "brakes" that permit the immune system to fight the cancer cells. The epigenetic inhibitor drug entinostat has been shown in preclinical models and laboratory studies (which led to this current clinical trial) to drive changes in the chemical environment of cells to make them more amenable to immunotherapy, said Vered Stearns, MD, Director of the Women's Malignancies Disease Group at the Johns Hopkins Kimmel Cancer Center.


The authors found that the objective response rate was 16 percent. One patient with triple-negative breast cancer had a complete response. Because the cancer types included in the study are not known to have high response rates to immune checkpoint therapy, these preliminary results are very promising. Treatment-related adverse events were mostly low-grade, and included fatigue, nausea, anemia, and diarrhea. These results were published online in Clinical Cancer Research (2021; doi: 10.1158/1078-0432.CCR-20-5017).


Study co-author Evanthia T. Roussos Torres, MD, PhD, Adjunct Professor at Johns Hopkins, Assistant Professor at the University of Southern California's Keck School of Medicine, and oncologist and researcher with USC's Norris Comprehensive Cancer Center in Los Angeles, noted that the entinostat functioned as an immune system-priming agent prior to using immunotherapy in solid tumors that traditionally are nonresponsive to checkpoint inhibition therapy.


"One of the major findings of our study is that this is a safe and tolerable combination of therapies," she said. "There aren't very many trials investigating dual immune checkpoint inhibition in combination with other novel therapeutics. We determined a safe, tolerable dose with this combination that had very few adverse effects. That is significant."


Study Details

The researchers collected blood and tumor samples from the 33 patients before and after the 2 weeks of entinostat to assess the impact of the entinostat on the immune system, and also after the addition of the immune checkpoint agents to evaluate the effect of each of the treatments on the immune environment. The study team found a significant increase in the ratio of CD8/FoxP3 gene expression in tumors following checkpoint inhibitor treatment but not after entinostat treatment alone. This suggests that the combination therapy helped increase both cytotoxic immune system T cells, as well as decrease immune system T regulatory cells, which equaled a stronger immune response, Roussos Torres explained.


The median age of participants was 60, most (91%) were female, 30 percent had breast cancer (the main tumor type studied), and the median number of prior regimens tried for their disease was 3.5. The median progression-free survival, or time until disease progression or death, was 6.1 months, and median overall survival was 10.6 months. Stable disease, considered the best response, was observed in 44 percent of participants. Clinical benefit rate was 60 percent.


The most robust increases in CD8/FoxP3 ratio were observed in two patients with HR-positive breast cancer who experienced a partial response and stable disease. Three additional patients who experienced stable disease had adenocarcinoma.


The complete response in a patient with breast cancer "is a promise that there may be a role for this combination of therapies in breast cancers," said senior study author Roisin M. Connolly, MBBCh, MD, Adjunct Professor at Johns Hopkins and Chair in Cancer Research at the University College Cork and Cork University Hospital in Ireland. "Immunotherapy hasn't been as big a blockbuster to date in advanced breast cancer as in other cancers, such as lung cancer or melanoma. This study paves the way for novel combination therapies that have the potential to improve response rates to immune checkpoint inhibitors in traditionally less-responsive tumor types."


This drug combination is being investigated further in a group of 24 patients with HER2-negative breast cancer as part of the same NCI-sponsored clinical trial. "We are excited to have completed accrual to these ongoing studies in advanced HER2-negative breast cancer, and expect to report on these findings later this year," Stearns noted.