In a new study on mice, scientists at the Washington University School of Medicine in St. Louis show targeting a master kinase that drives innate immunity and inflammation, makes hard-to-treat pancreatic cancers more sensitive to chemotherapy and checkpoint immunotherapy.

Targeting the kinase IRAK4, the researchers show, overcomes immune suppression, decreases fibrosis within tumors and activates immune T cells that infiltrate into tumors, to make pancreatic cancers that are notorious for their resistance to treatments, more accessible to existing and emerging treatment paradigms. In mice, the therapy more than doubled survival of pancreatic cancer models, the authors report.

The preclinical findings were published on March 7, 2022, in the journal Gastroenterology, in an article titled “IRAK4 signaling drives resistance to checkpoint immunotherapy in pancreatic ductal adenocarcinoma,” bolster the rationale for a national clinical trial that will evaluate the safety and efficacy of an IRAK4 inhibitor therapy in about 50 patients with pancreatic ductal adenocarcinoma (PDAC). The national trial includes more than 30 clinical centers in the U.S. and Canada and is part of the National Cancer Institute’s (NCI) Experimental Therapeutics Clinical Trials Network. The trial will be led by researchers at the Siteman Cancer Center at the Barnes-Jewish Hospital, Washington University and Washington University School of Medicine.

Kian-Huat Lim, MD, PhD, an associate professor of medicine at the Washington University School of Medicine in St. Louis is the a senior author of the study.

Kian-Huat Lim, MD, PhD, an associate professor of medicine, principal investigator for translational science on the national trial, and a senior author of the current study said, “With this therapy, we are going after a pathway that we know is involved in driving the aggressiveness of pancreatic cancer. The results of this study are promising in that it showed a way to break through the defenses of this tumor type, making it susceptible to our therapeutics, including combinations of chemotherapy and newer immunotherapies that stimulate T cells to fight the cancer.”

Lim’s team, including Vikas Somani, PhD, a postdoctoral research associate in Lim’s lab, found IRAK4 drives inflammation in pancreatic tumors and leads to a phenomenon called  “T cell exhaustion” where T cells no longer attack aberrant cells such as cancer cells, as they should.

The team used an established and clinically relevant mouse model of PDAC called the KPC mouse that develops many key features seen in human PDAC such as microscopic lesions of the pancreas (pancreatic intraepithelial neoplasia) and inflammation.

The researchers treated KPC mice with an IRAK4 inhibitor, called CA-4948 which is the only IRAK4 inhibitor that is part of a national clinical trial for blood cancers (NCT03328078).

They found the treatment reduced in inflammatory signaling in the tumors, increased the ability of immune T cells to infiltrate into the tumors, and sensitized the tumors to checkpoint immunotherapy that potentiates the activity of T cells. CA-4948 blocks the activation of the NF-κB signaling pathway that drives cancer.

New research shows, blocking a major inflammatory pathway in pancreatic cancer makes the tumors sensitive to chemotherapy and checkpoint immunotherapy. The image show pancreatic cancer cells in green and T cells are in red [Lim Lab].
Treatment with CA-4948 or selective deletion of IRAK4, the authors show, increases survival in KPC mice compared to chemotherapy or placebo controls. The IRAK4 inhibitor when used in combination with either chemotherapy or checkpoint immunotherapy, further improved survival.

The team conducted single cell RNAseq analysis and found IRAK4 inhibition reprogrammed cancer-associated fibroblasts toward acute inflammatory responses. This, the authors suspect, may reflect the conversion of an intractable or “cold” tumor into a “hot“ or targetable tumor.

Haeseong Park, MD, an associate professor of medicine and a principal investigator of the new trial said, “We look forward to beginning the national clinical trial of this drug in patients with pancreatic cancer—the trial is a direct translation of this particular paper.”

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