Inflammation in the blood could be a new biomarker to help identify patients with advanced pancreatic cancer who do not respond to the immune stimulating drugs called CD40 agonists, suggests a new study by researchers at Abramson Cancer Center in the University of Pennsylvania. published in JCI Vision.
Pancreatic cancer is known to cause inflammation of systemic inflammation, which is easily found in the blood. The team found that patients with systemic inflammation had worse overall survival rates than patients without inflammation when treated with both a CD40 agonist and the chemcitabine chemotherapy.
The purpose of CD40 agonists is to help “push the gas” on the immune system both by activating antigen-presenting cells, such as dendritic cells, to “prime” T cells and by increasing macrophage activity against tumor. However, CD40 agonist treatments only reduce tumors in just over half of patients, previous studies have shown. Now, identifying systemic inflammation as a means of protection against future treatment decisions and studies could lead to it, as well as offer new targets for researchers to study.
CD40 is a very interesting target, especially in pancreatic cancer, where monoclonal agonistic antibodies have promised promise, but we know that these agonists still have barriers in some patients who are weakening the intended effects of the drug. We believe that we have not only identified a potentially strong biomarker, but also important players in the defense system that we have not seen before that may be leading defenses. “
Max M. Wattenberg, MD, Lead Author, Clinical Professor of Medicine, Department of Hematology-Oncology, Perelman School of Medicine at the University of Pennsylvania
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is currently the third leading cause of cancer deaths in the United States. Despite accounting for only about three percent of new cancer cases, it accounts for more than seven percent of cancer deaths, and only 10 percent of patients live five years with the disease.
The researchers analyzed blood samples from 22 patients with PDAC to understand the immune mechanisms undergoing treatment with chemoimmunotherapy. The team observed an overgrowth of B cells, monocytes, and dendritic cells as well as CD4 + T cell activation over eight days in the majority of patients. Surprisingly, a closer look showed no consistent evidence of CD8 + cell activation and no association between T cell activity and outcomes. These findings challenge preclinical studies that have suggested that T cell activation induced by CD40 agonists would be linked to outcomes.
Instead, overall survival results were related to a measurable feature in the blood of patients detected before treatment: systemic inflammation. Systemic inflammation is characterized by an increased presence of neutrophils, inflammatory cytokines (including IL-6 and IL-8) and acute blood-cell permeability reactors, and is a well-known symptom of pancreatic cancer and other types of cancer .
Patients with systemic inflammation before treatment with a CD40 agonist and gemcitabine, the authors report, had a median total survival of 5.8 months versus 12.3 months for patients without inflammation from the start of treatment.
Also surprising, the data suggest that chemcitabine chemotherapy may destroy monocytes and dendritic cells, which are fundamental for enabling T cell immune responses. However, the team has previously shown that a CD40 agonist can PDAC sensitivity to chemcitabine chemotherapy, and therefore, T cells may not always be required for successful results with treatment using CD40 agonists in combination with chemotherapy.
“These latest findings support the fact that inflammation appears to undermine the immune system and in doing so limits the ability of immunosuppressive therapies to be compromised. working, “said senior author Gregory L. Beatty, MD, PhD, associate professor of Hematology- Oncology at Penn Perelman School of Medicine.” Next, we are interested in finding out how you combine a T-cell immune response with a CD40 agonist, so we study a combination that helps to lower the inflammatory response and make the parts of the immune system more capable of stimulating T- cell response. . “
Source:
University of Pennsylvania School of Medicine
Magazine Reference:
Wattenberg, MM, et al. (2021) Systemic inflammation is a test of results to CD40-based agonist therapy in pancreatic cancer patients. JCI Vision. doi.org/10.1172/jci.insight.145389.